Prodrugs of tetrahydrocannabinol, compositions comprising prodrugs of tetrahydrocannabinol and methods of using the same

ABSTRACT

Described herein are Δ9-THC prodrugs, methods of making Δ9-THC prodrugs, formulations comprising Δ9-THC prodrugs and methods of using Δ9-THC. One embodiment described herein relates to the transdermal administration of a Δ9-THC prodrug for treating and preventing diseases and/or disorders.

CROSS REFERENCE TO RELATED APPLICATION

This Application is a divisional of U.S. application Ser. No.12/326,036, filed Dec. 1, 2008, now U.S. Pat. No. 8,227,627, and claimsthe benefit of U.S. Provisional Application Ser. Nos. 60/991,555, filedNov. 30, 2007, and 61/037,568, filed Mar. 18, 2008, which are herebyincorporated by reference.

FIELD

Described herein are pharmaceutically active agents suitable forpharmaceutical use such as transdermal delivery to a mammal,compositions for transdermal delivery of pharmaceutically active agentsand the use of such compositions in treating diseases and disorders.

BACKGROUND

Pain is the most frequently reported symptom and it is a common clinicalproblem which confronts the clinician. Millions of people in the USAsuffer from severe pain that, according to numerous recent reports, ischronically under-treated or inappropriately managed. Similarly,millions of people also suffer from severe nausea and/or frequentemesis. Moreover, all too frequently, many patients suffering fromchronic, under-treated or unretractable pain, also suffer from lack ofappetite, nausea and/or frequent emesis, such that a patient is unableto receive effective therapeutic doses of oral pain medications, therebyexacerbating their pain.

The clinical usefulness of the cannabinoids, includingΔ⁹-tetrahydrocannabinol (Δ⁹-THC), to provide analgesia, help alleviatenausea and emesis, as well as stimulate appetite has beenwell-recognized.

A “wasting syndrome” generally describes a clinical syndrome in which anindividual has lost more than 10% of his or her body weight in theabsence of active infections or any other identifiable cause of weightloss. The weight loss exemplified in a wasting syndrome can result frommalabsorption, diarrhea, reduced food intake or altered metabolism.While wasting syndromes can present secondarily to many illnesses andconditions, it frequently develops as a co-morbid condition, secondaryto chemotherapy and human immunodeficiency virus infection (a.k.aHIV-wasting). Cannabinoids, such as Δ⁹-THC, are effective in treatingand alleviating wasting syndromes, including, but not limited toHIV-wasting and chemotherapy induced wasting. Indeed, Δ⁹-THC iscurrently available in an oral dosage, sold under the trade nameMarinol®, to treat this indication.

Anorexia is a depressed sensation of appetite. In severe cases, anindividual with anorexia can experience a clinically significant loss inbody weight. Anorexia can appear as a secondary symptom to manydisorders including severe depression, cancer, Crohn's disease,ulcerative colitis, dementia, superior mesenteric artery syndrome andchronic renal failure. Anorexia can also result from the use of certaindrugs, particularly stimulants and narcotics such as cocaine and heroin.Anorexia nervosa, is a specific type of anorexia, which is a psychiatricdisorder, describing an eating disorder, characterized by low bodyweight and body image distortion, with an obsessive fear of gainingweight. Administration of Δ⁹-THC can increase the appetite ofindividuals experiencing anorexia that has resulted in clinicallysignificant loss in weight, including individuals suffering fromanorexia nervosa, as well individuals with anorexia secondary to eitheranother diagnosis or drug use.

A notable percentage of the U.S. population satisfy the diagnosticcriteria for alcohol use disorders (“AUDs”). The consumption ofexcessive amounts of alcohol results in a complex array ofpharmacological effects that directly impact the ability to treat thecondition. These effects directly impact the brain and includeprogressive neurodegenration, impaired executive function and dependenceleading to withdrawal-induced negative effects. It is known that thecannabinoids, including Δ⁹-THC and Δ⁹-THC prodrugs have neuroprotective,anxiolytic and anti-convulsant effects, which may be effective inpreventing additional brain damage in persons with AUDs, whilesimultaneously decreasing the frequency of relapses.

Dystonia is a neurological movement disorder, with many known causes,and characterized by involuntary, continual muscular contractionscausing twisting and repetitive movements or abnormal postures.Cannabinoids have been shown to reduce the symptoms of muscularcontractions characterizing this disorder.

The etiological pathology of many diseases relates to the inflammatoryprocesses caused by an individual's immune system. The inflammation mayresult from (1) an otherwise appropriate immunoresponse to an outsidetrauma, such as brain swelling secondary to a closed head injury; (2) anoveractive immunoresponse such as with an allergic reaction ordermatitis; or (3) an inappropriate auto-immunoresponse such as whatcauses certain forms of multiple sclerosis, inflammatory bowel disordersand arthritis. Regardless of the underlying cause of the inflammation,it is therapeutically desirable under these circumstances to regulate tothe immune system and lessen the inflammatory response. Cannabinoidshave been shown to regulate various steps in the immune response andhave shown some therapeutic benefit in treatment of certain inflammatorydiseases such as dermatitis and psoriasis.

Rheumatoid arthritis affects approximately 0.5-1% of the United Statespopulation, and autoimmune diseases in general affect more than 20million Americans. The pain associated with rheumatoid arthritis canoften be disabling. Cannabinoids, such as Δ⁹-THC, have been found to beuseful as adjunct treatment for rheumatoid arthritis and joint painsecondary to other autoimmune diseases, such as inflammatory boweldisease, multiple sclerosis and systemic lupus erythematosus.

Chronic abusers of cannabis can develop dependence and experiencewithdrawal symptoms when they attempt to discontinue use of the drug.Collectively cannabis dependence and withdrawal are referred to hereinas cannabis use disorders. It is known in the skill of the art thatcannabinoids, including Δ⁹-THC, are useful in the treating cannabis usedisorders.

In addition to the above-discussed therapeutics benefits, cannabinoidssuch as Δ⁹-THC, and Δ⁹-THC prodrugs, offer a variety of pharmacologicalbenefits, including, but not limited to, anti-inflammatory,anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective,substitution therapy for marijuana abuse and immunomodulatory effects.

Given the therapeutic benefit, it would be advantageous to develop acomposition in which Δ⁹-THC is delivered systemically to achieve atherapeutically effective dose. Unfortunately, as with the othercannabinoids, Δ⁹-THC undergoes substantial first-pass metabolism whenabsorbed from the human gut after oral administration. Further, the oralbioavailability of any Δ⁹-THC-containing product is further diminishedwhen a patient suffers from nausea or emesis, as they avoid eithertaking their oral medication or the oral dosage form does not remain intheir gastro-intestinal tract for a sufficient time to achieve atherapeutic dose. Additionally, due to its highly hydrophobic nature,Δ⁹-THC is poorly absorbed through membranes such as the skin of amammal, such as a human. Therefore, the success of transdermallyadministering therapeutically effective quantities of Δ⁹-THC to a mammalin need of such treatment within a reasonable time frame and over asuitable surface area has been substantially limited.

Therefore, in view of the foregoing, it would be desirable to delivertherapeutically effective amounts of Δ⁹-THC to a mammal in need thereoffor the treatment of one or more medical conditions, such as pain,nausea or appetite stimulation, by a route of administration that doesnot depend upon absorption from the gastrointestinal tract of the mammaland not subject to first-pass metabolism upon absorption from thegastrointestinal tract. One such route of administration for thesystemic delivery of Δ⁹-THC is transdermal.

Unfortunately, due to its highly hydrophobic nature, Δ⁹-THC is poorlyabsorbed through membranes such as the skin of a mammal, such as ahuman. Therefore, the success of transdermally administeringtherapeutically effective quantities of Δ⁹-THC to a mammal in need ofsuch treatment within a reasonable time frame and over a suitablesurface area has been substantially limited.

The epidermis and dermis of many mammals, such as humans and guineapigs, contains enzymes which are capable of metabolizing activepharmaceutical agents which pass through the stratum corneum. Themetabolic process occurring in the skin of mammals, such as humans, canbe utilized to deliver pharmaceutically effective quantities of Δ⁹-THCto a mammal in need thereof. Described herein are prodrugs of Δ⁹-THCthat can be transdermally administered to a mammal, such as a human, sothat the metabolic product resulting from metabolism in the skin isΔ⁹-THC which is systemically available for the treatment of a medicalcondition such as pain, nausea or appetite stimulation. Also describedherein are compositions comprising Δ⁹-THC prodrugs suitable fortransdermal delivery to a mammal in need thereof and methods of usingΔ⁹-THC prodrugs.

Therefore, a significant advancement in the art would occur if a prodrugof Δ⁹-THC capable of transdermal delivery, compositions suitable fortransdermal delivery comprising prodrugs of Δ⁹-THC and methods of usingprodrugs of Δ⁹-THC could be developed whereby the resulting metabolicproduct was Δ⁹-THC which is systemically available to a mammal in atherapeutically effective amount.

In addition, pharmaceutical compositions can be systemicallyadministered by other means, including: oral, buccal, sublingual,injection, rectal, vaginal and intranasal. The metabolic processoccurring in mammals, such as humans, can also be utilized to deliverpharmaceutically effective quantities of Δ⁹-THC to the systemiccirculation of a mammal in need thereof. Described herein are prodrugsof Δ⁹-THC that can be administered to a mammal, such as a human, so thatthe metabolic product resulting from metabolism in the skin is Δ⁹-THCwhich is available for the treatment of a medical condition such aspain, nausea or appetite stimulation. Also described herein arecompositions comprising Δ⁹-THC prodrugs suitable for delivery to amammal in need thereof and methods of using Δ⁹-THC prodrugs.

Therefore, a significant advancement in the art would occur if one coulddevelop a prodrug of Δ⁹-THC capable of oral, buccal, sublingual,injectable, topical, follicular, nasal, ocular, rectal or vaginaldelivery; compositions suitable for oral, buccal, sublingual,injectable, topical, follicular, nasal, ocular, rectal, vaginal deliverycomprising prodrugs of Δ⁹-THC; and methods of using prodrugs of Δ⁹-THCwhereby the resulting metabolic product was Δ⁹-THC which is systemicallyavailable to a mammal in a therapeutically effective amount.

In addition to the benefits of systemically administered Δ⁹-THCdiscussed above, cannabinoids, including Δ⁹-THC, have been found to havelocalized benefits from topical administration. For example, topicallyadministered cannabinoids have been found to be useful to alleviate painand other conditions originating near the surface of the skin, includingbut not limited to pain associated with post-herpetic neuralgia,shingles, burns, actinic keratosis, oral cavity sores and ulcers,post-episiotomy pain, psoriasis, pruritis, contact dermatitis, eczema,bullous dermatitis herpetiformis, exfoliative dermatitis, mycosisfungoides, pemphigus, severe erythema multiforme (e.g., Stevens-Johnsonsyndrome), seborrheic dermatitis and psoriatic arthritis. In addition,topically administered cannabinoids have been found to be useful toalleviate pain and other conditions associated with deeper tissues, suchas peripheral neuropathic pain, including but not limited to theperipheral neuropathic pain associated with diabetic neuropathy,ankylosing spondylitis, Reiter's syndrome, gout, chondrocalcinosis,joint pain secondary to dysmenorrhea, fibromyalgia, musculoskeletalpain, neuropathic-postoperative complications, polymyositis, acutenonspecific tenosynovitis, bursitis, epicondylitis, post-traumaticosteoarthritis, synovitis, and juvenile rheumatoid arthritis. Whencannabinoids are administered topically to treat pain and otherconditions associated with deeper tissues, including peripheralneuropathic pain, it maybe useful to co-administer cannabinoidssystemically.

In order to achieve these local benefits, it is advantageous for Δ⁹-THCor a prodrug thereof to penetrate the stratum corneum but not beabsorbed systemically. In such a case, the Δ⁹-THC would concentrate inthe skin and/or pilosebaceous unit, thus maximizing its local effect.Not only does the localized effect increase the potential therapeuticbenefit, it lessens the frequency and severity of side-effectsassociated with cannabinoid administration because the amount of activecompound circulating in the patient is minimized. The Δ⁹-THC can beincorporated into a prodrug with an active moiety that would improve theappearance and/or hydration of the skin.

Therefore, a significant advancement in the art would occur with thedevelopment of a Δ⁹-THC prodrug capable of topical delivery, such thatit penetrates the outer layer of the skin but is not absorbed intocirculation; compositions suitable for topical delivery comprisingprodrugs of Δ⁹-THC and methods of using prodrugs of Δ⁹-THC whereby theresulting metabolic product was Δ⁹-THC which is available at the site ofadministration in a mammal in a therapeutically effective amount but isnot absorbed systemically.

SUMMARY

Described herein are prodrugs of Δ⁹-THC, methods of making prodrugs ofΔ⁹-THC, compositions comprising prodrugs of Δ⁹-THC and methods of usingprodrugs of Δ⁹-THC.

Other embodiments, objects, features and advantages will be set forth inthe detailed description of the embodiments that follows, and in partwill be apparent from the description, or may be learned by practice, ofthe claimed invention. These objects and advantages will be realized andattained by the processes and compositions particularly pointed out inthe written description and claims hereof. The foregoing Summary hasbeen made with the understanding that it is to be considered as a briefand general synopsis of some of the embodiments disclosed herein, isprovided solely for the benefit and convenience of the reader, and isnot intended to limit in any manner the scope, or range of equivalents,to which the appended claims are lawfully entitled.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=2), ALL00120 (n=3), ALL00121 (n=2) andALL00123 (n=3) with 2.36:1.18:1 PG(propylene glycol):ethanol:H₂O donorsolution, wherein “n” is the number of samples tested.

FIG. 2 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=2), ALL00121 (n=2) and ALL00123 (n=3) withgel formulation, wherein “n” is the number of samples tested.

FIG. 3 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=2), ALL00122 (n=2), and ALL00124 (n=2) with2.36:1.18:1 pH=5.5 PG(propylene glycol):ethanol:H₂O donor solution,wherein “n” is the number of samples tested.

FIG. 4 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=3), ALL00124 (n=2), and ALL00125 (n=3) with2.36:1.18:1 pH=5.5 PG(propylene glycol):ethanol:H₂O donor solution,wherein “n” is the number of samples tested.

FIG. 5 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=3), ALL00153 (n=3), and ALL00154 (n=1) withgel formulation, wherein “n” is the number of samples tested.

FIG. 6 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=2), ALL00117 (n=3), ALL00118 (n=3) andALL00126 (n=2) with 90:8:2 PG(propylene glycol):H2O:IPM donor solution,wherein “n” is the number of samples tested.

FIG. 7 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=1), ALL00129 (n=3), and ALL00138 (n=2) with90:8:2 PG(propylene glycol):H2O:IPM donor solution, wherein “n” is thenumber of samples tested.

FIG. 8 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=2), ALL00127 (n=3), ALL00134 (n=3), andALL00144 (n=2) with 90:8:2 PG(propylene glycol):H2O:IPM donor solution,wherein “n” is the number of samples tested.

FIG. 9 is a plot of the representative permeation profile ofΔ⁹-tetrahydrocannabinol (n=2) and ALL00153 (n=3) in 90:8:2 PG(propyleneglycol):H₂O:IPM donor solution, wherein “n” is the number of samplestested.

FIG. 10 is a table of Δ⁹-Tetrahydrocannabinol andΔ⁹-tetrahydrocannabinol prodrugs Log P values. The Log P valuesrepresent the water/octanol partition coefficient and are calculatedChemSketch version 10.02 (Advanced Chemistry Development; Toronto,Ontario, Canada).

DESCRIPTION

While the present invention is capable of being embodied in variousforms, the description below of several embodiments is made with theunderstanding that the present disclosure is to be considered as anexemplification of the claimed subject matter, and is not intended tolimit the appended claims to the specific embodiments illustrated. Theheadings used throughout this disclosure are provided for convenienceonly and are not to be construed to limit the claims in any way.Embodiments illustrated under any heading may be combined withembodiments illustrated under any other heading.

Compounds described herein include pharmaceutically acceptable prodrugsof Δ⁹-THC. One embodiment described herein includes pharmaceuticallyacceptable prodrugs of Δ⁹-THC which are suitable for transdermaladministration and are metabolized to Δ⁹-THC. A further embodimentincludes pharmaceutically acceptable prodrugs of Δ⁹-THC which aresuitable for any route of administration. The pharmaceuticallyacceptable prodrugs of Δ⁹-THC may be in any suitable form foradministration to a mammal such as in the form of a free base, freeacid, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer,tautomer, polymorph, derivative, or the like, provided that the freebase, salt, ester, hydrate, anhydrate, amide, enantiomer, isomer,tautomer, or any other pharmacologically suitable derivative istherapeutically active or undergoes conversion within or outside of thebody to a therapeutically active form of Δ⁹-THC.

Compositions described herein comprise at least one pharmaceuticallyacceptable prodrug of Δ⁹-THC. The pharmaceutically acceptable prodrugsof Δ⁹-THC may be in any suitable form for administration to a mammalsuch as in the form of a free base, free acid, salt, ester, hydrate,anhydrate, amide, enantiomer, isomer, tautomer, polymorph, derivative,or the like, provided that the free base, salt, ester, hydrate,anhydrate, amide, enantiomer, isomer, tautomer, or any otherpharmacologically suitable derivative is therapeutically active orundergoes conversion within or outside of the body to a therapeuticallyactive form of Δ⁹-THC.

Compositions described herein include those which are suitable fortransdermal, oral, buccal, sublingual, injectable, follicular, topical,nasal, ocular, rectal or vaginal administration of prodrugs of Δ⁹-THC.The compositions described herein optionally include a vehicle orcarrier for the transdermal administration of a prodrug of Δ⁹-THC aswell as optionally including solvents, thickening agents, penetrationenhancers, wetting agents, lubricants, emollients, substances added tomask or counteract a disagreeable odor, fragrances, and substances addedto improve appearance or texture of the composition.

The term prodrug as used herein refers to a compound that undergoes achemical conversion, through a metabolic process or otherwise within thebody of the mammal receiving the compound, into its active form that hasmedical effects.

In one embodiment, illustrative Δ⁹-THC prodrugs include those compoundsof Formula (I):

wherein

R₁ is comprised of a bio-labile linker (e.g. ester, oxygenated ester,oxaester, pegylated ester, hydroxylated ester, branched hydroxylatedester, succinic acid monoester, oxalic acid mixed pegylated ester, aminoester, cyclic amino ester, acylated amino ester, carbonate, oxygenatedcarbonate, oxacarbonate, pegylated carbonate, hydroxylated carbonate,branched hydroxylated carbonate, aminoalkyl carbonate, cyclic aminoalkylcarbonate, acylated aminoalkyl carbonate, hydroxycarbonylalkylcarbonate, carbamate, alkyl carbamate, aminoalkyl carbamate, acylatedaminoalkyl carbamate, cyclic aminoalkyl carbamate, oxacarbamate,pegylated carbamate, hydroxylated carbamate, branched hydroxylatedcarbamate, hydroxycarbonylalkyl carbamate, phosphate, diphosphate,triphosphate or other suitable bio-labile linking structure) and furthercomprising moieties which can be selected in order to control the rateand extent of absorption and metabolism, such as transdermal absorptionand metabolism. Several options for R₁ are disclosed herein. Alsoincluded herein is the free acid, free base, salt, ester, hydratedforms, anhydrous, amide, enantiomer, isomer, tautomer, polymorph, orderivative thereof of compounds of Formula I.

Additional embodiments contemplated by the present disclosure include,but are not limited to, those described in WO2007044215, WO2007035945,US2007066657, WO2007026215, WO2007020502, WO2007017264, WO2007009720,US2007004772, US2006287324, US2006287323, US2006287342, US2006287341,US2006089378, US2006079556, US2005143441, U.S. Pat. No. 7,109,216,US2004235854, US2005267161, US2005054659, US2007099990, US2006122229,US2006122230, US2004077650, U.S. Pat. No. 6,974,810, US2004248944, U.S.Pat. No. 6,977,266 and US2006052411 and U.S. patent application Ser. No.10/032,163.

“Pharmaceutically acceptable salts,” or “salts,” include the salt of aΔ⁹-THC prodrug suitable for administration to a mammal and includesthose prepared from formic, acetic, propionic, succinic, glycolic,gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, maleic,fumaric, pyruvic, aspartic, glutamic, benzoic, anthranilic, mesylic,stearic, salicylic, p-hydroxybenzoic, phenylacetic, mandelic, embonic,methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic,toluenesulfonic, 2-hydroxyethanesulfonic, sulfanilic,cyclohexylaminosulfonic, algenic, beta.-hydroxybutyric, galactaric andgalacturonic acids. The following list of pharmaceutically acceptablesalts is not meant to be exhaustive but merely illustrative as person ofordinary skill in the art would appreciate that other pharmaceuticallyacceptable salts of Δ⁹-THC and prodrugs of Δ⁹-THC may be prepared.

In one embodiment, acid addition salts are prepared from the free baseforms using conventional methodology involving reaction of the free basewith a suitable acid. Suitable acids for preparing acid addition saltsinclude both organic acids, e.g., acetic acid, propionic acid, glycolicacid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinicacid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoicacid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonicacid, p-toluenesulfonic acid, salicylic acid, and the like, as well asinorganic acids, e.g., hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid, and the like. The following list oforganic and inorganic acids is not meant to be exhaustive but merelyillustrative as person of ordinary skill in the art would appreciatethat other acids may be used to create pharmaceutically acceptable saltsof Δ⁹-THC and prodrugs of Δ⁹-THC. In other embodiments, an acid additionsalt is reconverted to the free base by treatment with a suitable base.In still other embodiments, the basic salts are alkali metal salts,e.g., sodium salt.

In one embodiment, R₁ is an ester. The preparation of Δ⁹-THC estersinvolves functionalizing the hydroxyl group that is present within themolecular structure of Δ⁹-THC. In another embodiment, the ester of R₁ isoxygenated. In another embodiment, R₁ is an oxygenated ester which is anoxaester. In another embodiment, R₁ is an oxaester which is pegylated.In further embodiments, R₁ is a pegylated oxaester that can have 1ethylene glycol repeat unit, 2 ethylene glycol repeat units, 3 ethyleneglycol repeat units, 4 ethylene glycol repeat units, 5 ethylene glycolrepeat units, 6 ethylene glycol repeat units, 7 ethylene glycol repeatunits, 8 ethylene glycol repeat units, 9 ethylene glycol repeat units,10 ethylene glycol repeat units, 11 ethylene glycol repeat units, 12ethylene glycol repeat units, 13 ethylene glycol repeat units, 14ethylene glycol repeat units and 15 ethylene glycol repeat units. In afurther embodiment, R₁ is an ester which is hydroxylated. In a furtherembodiment, R₁ is a branched hydroxylated ester. In a furtherembodiment, R₁ is ester which is an alkyl ester. In additionalembodiments, R₁ is an alkyl ester having 1 alkyl carbon, 2 alkylcarbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkylcarbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkylcarbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkylcarbons and 15 alkyl carbons.

In other embodiments, R₁ is an ester which is an amino ester having 1amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5 aminogroups. In another embodiment, R₁ is an amino ester which is aminoalkylester. In another embodiment, R₁ is an amino ester which is cyclic aminoester. In a further embodiment, R₁ is an aminoalkyl ester having 1 aminogroup, 2 amino groups, 3 amino groups, 4 amino groups and 5 amino groupsand having 1 alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkylcarbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkylcarbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkylcarbons, 13 alkyl carbons, 14 alkyl carbons and 15 alkyl carbons. Inanother embodiment, R₁ is an amino ester which is an acylated aminoester. In a further embodiment, R₁ is a succinic acid monoester. In afurther embodiment, R₁ is an oxalic acid mixed pegylated ester.

In one embodiment, R₁ is a carbamate. The preparation of Δ⁹-THCcarbamates involves functionalizing the hydroxyl group that is presentwithin the molecular structure of Δ⁹-THC. In a further embodiment, R₁ isa carbamate which is an alkyl carbamate. In additional embodiments, R₁is an alkyl carbamate having 1 alkyl carbon, 2 alkyl carbons, 3 alkylcarbons, 4 alkyl carbons, 5 alkyl carbons, 6 alkyl carbons, 7 alkylcarbons, 8 alkyl carbons, 9 alkyl carbons, 10 alkyl carbons, 11 alkylcarbons, 12 alkyl carbons, 13 alkyl carbons, 14 alkyl carbons and 15alkyl carbons. In other embodiments, R₁ is a carbamate which is an aminocarbamates having 1 amino group, 2 amino groups, 3 amino groups, 4 aminogroups and 5 amino groups. In another embodiment, R₁ is an aminocarbamate which is an alkylamino carbamate. In a further embodiment, R₁is an alkylamino carbamate having 1 amino group, 2 amino groups, 3 aminogroups, 4 amino groups and 5 amino groups and independently having 1alkyl carbon, 2 alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkylcarbons, 6 alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkylcarbons, 10 alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkylcarbons, 14 alkyl carbons and 15 alkyl carbons. In an additionalembodiment, R₁ is a cyclic aminoalkyl carbamate. In another embodiment,R₁ is a carbamate that is oxygenated. In another embodiment, R₁ is anoxygenated carbamate which is an oxacarbamate. In another embodiment, R₁is an oxacarbamate that is pegylated. In further embodiments, R₁ is apegylated oxacarbamate that can have 1 ethylene glycol repeat unit, 2ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethyleneglycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycolrepeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeatunits, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units,11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13ethylene glycol repeat units, 14 ethylene glycol repeat units and 15ethylene glycol repeat units. In a further embodiment, R₁ is acarbamates which is hydroxylated. In a further embodiment, R₁ is abranched hydroxylated carbamate. In another embodiment, R₁ is ahydroxycarbonyl carbamate.

In one embodiment, R₁ is a carbonate. The preparation of Δ⁹-THCcarbonates involves functionalizing the hydroxyl group that is presentwithin the molecular structure of Δ⁹-THC. In another embodiment, thecarbonate of R₁ is oxygenated. In another embodiment, R₁ is anoxygenated carbonate which is an oxacarbonate. In another embodiment, R₁is an oxacarbonate which is pegylated. In further embodiments, R₁ is apegylated oxacarbonate that can have 1 ethylene glycol repeat unit, 2ethylene glycol repeat units, 3 ethylene glycol repeat units, 4 ethyleneglycol repeat units, 5 ethylene glycol repeat units, 6 ethylene glycolrepeat units, 7 ethylene glycol repeat units, 8 ethylene glycol repeatunits, 9 ethylene glycol repeat units, 10 ethylene glycol repeat units,11 ethylene glycol repeat units, 12 ethylene glycol repeat units, 13ethylene glycol repeat units, 14 ethylene glycol repeat units and 15ethylene glycol repeat units. In a further embodiment, R₁ is a carbonatewhich is hydroxylated. In a further embodiment, R₁ is a carbonate whichis hydroxylated. In a further embodiment, R₁ is a branched hydroxylatedcarbonate. In another embodiment, R₁ is a hydroxycarbonyl carbonate. Inother embodiments, R₁ is a carbonate which is an amino carbonates having1 amino group, 2 amino groups, 3 amino groups, 4 amino groups and 5amino groups. In another embodiment, R₁ is an amino carbonates which arealkylamino carbonates. In a further embodiment, R₁ is an aminoalkylcarbonate having 1 amino group, 2 amino groups, 3 amino groups, 4 aminogroups and 5 amino groups and independently having 1 alkyl carbon, 2alkyl carbons, 3 alkyl carbons, 4 alkyl carbons, 5 alkyl carbons, 6alkyl carbons, 7 alkyl carbons, 8 alkyl carbons, 9 alkyl carbons, 10alkyl carbons, 11 alkyl carbons, 12 alkyl carbons, 13 alkyl carbons, 14alkyl carbons and 15 alkyl carbons.

In one embodiment, R₁ is a phosphate. The preparation of Δ⁹-THCphosphates involves functionalizing the hydroxyl group that is presentwithin the molecular structure of Δ⁹-THC. In this case, the Δ⁹-THCphosphate was isolated in the form of ammonium salt. However, thoseskilled in the art can convert Δ⁹-THC phosphate to a salt of apharmaceutically acceptable amine. In addition, those skilled in the artcan prepare salts in a different phosphate:amine ratio. As illustratedin the structure below, the Δ⁹-THC phosphate would have a structure of:

wherein X and Y, can be same or different, and are selected from a groupconsisting of: hydrogen, salt-forming cations including alkali metals(e.g., sodium and potassium), alkaline earth metals (e.g., calcium andmagnesium); and cations of pharmaceutically acceptable organic bases(e.g., quaternated or protonated amines, including alkylamines,hydroxyalkylamines, monoamines, diamines and naturally occurringamines). Examples of such pharmaceutically acceptable organic basesinclude choline, betaine, caffeine, N, N′-dibenzylethylenediamine,diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol,ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine,glucamine, hydrabamine, isopropylamine, methylglucamine, morpholine,piperidine, polyamine resins, procaine, purines, theobromine,triethylamine, trimethylamine, tripropylamine, tromethamine,tetramethylammonium hydroxide, benzyltrimethylammonium hydroxide,tris(hydroxymethyl)aminomethane (TRIS), N-(2-hydroxyethyl)pyrrolidine,piperazine, glucosamine, arginine, lysine and histidine. In a furtherembodiment, X and Y are different substituent groups. In anotherembodiment, X and Y are the same substituent group. In a furtherembodiment, X and Y can both be part of the same functional group, suchas piperazine.

In a further embodiment, the phosphate is selected from a groupconsisting of a diphosphate and triphosphate. In another embodiment, thecompound is the salt form of the di or tri phosphate.

Additional embodiments of Formula I include:

-   -   wherein X and Y is selected from a group consisting of:        hydrogen, salt-forming cations including alkali metals, alkaline        earth metals, and cations of pharmaceutically acceptable organic        bases.

Further embodiments described herein are pharmaceutical compositionscomprising:

-   -   (a) a Δ⁹-THC prodrug selected from the group consisting of:

wherein R₁ is selected from ester, oxygenated ester, oxaester, pegylatedester, hydroxylated ester, branched hydroxylated ester, succinic acidmonoester, oxalic acid mixed pegylated ester, amino ester, cyclic aminoester, acylated amino ester, carbonate, oxygenated carbonate,oxacarbonate, pegylated carbonate, hydroxylated carbonate, branchedhydroxylated carbonate, aminoalkyl carbonate, cyclic aminoalkylcarbonate, acylated aminoalkyl carbonate, hydroxycarbonylalkylcarbonate, carbamate, alkyl carbamate, aminoalkyl carbamate, acylatedaminoalkyl carbamate, cyclic aminoalkyl carbamate, oxacarbamate,pegylated carbamate, hydroxylated carbamate, branched hydroxylatedcarbamate, hydroxycarbonylalkyl carbamate, dihydrogen phosphate, alkalimetal phosphate salt, alkaline earth metal phosphate salt, and phosphatesalt of organic base; and

-   -   (b) a pharmaceutical excipient.

A method of administering a compound to a mammal comprising the stepsof:

-   -   (a) combining a compound selected from the group consisting of:

-   wherein R₁ is selected from ester, oxygenated ester, oxaester,    pegylated ester, hydroxylated ester, branched hydroxylated ester,    succinic acid monoester, oxalic acid mixed pegylated ester, amino    ester, cyclic amino ester, acylated amino ester, carbonate,    oxygenated carbonate, oxacarbonate, pegylated carbonate,    hydroxylated carbonate, branched hydroxylated carbonate, aminoalkyl    carbonate, cyclic aminoalkyl carbonate, acylated aminoalkyl    carbonate, hydroxycarbonylalkyl carbonate, carbamate, alkyl    carbamate, aminoalkyl carbamate, acylated aminoalkyl carbamate,    cyclic aminoalkyl carbamate, oxacarbamate, pegylated carbamate,    hydroxylated carbamate, branched hydroxylated carbamate,    hydroxycarbonylalkyl carbamate, dihydrogen phosphate, alkali metal    phosphate salt, alkaline earth metal phosphate salt, and phosphate    salt of organic base; and    with a pharmaceutical excipient to form a pharmaceutical    composition;    -   (b) creating a dosage form suitable for administration to a        mammal from the pharmaceutical composition; and    -   (c) administering the dosage form to a mammal.

Additional embodiments include methods of transdermally delivering aΔ⁹-THC prodrug to a mammal comprising the steps of:

-   -   (a) selecting a Δ⁹-THC prodrug from the group consisting of:

wherein R₁ is selected from ester, oxygenated ester, oxaester, pegylatedester, hydroxylated ester, branched hydroxylated ester, succinic acidmonoester, oxalic acid mixed pegylated ester, amino ester, cyclic aminoester, acylated amino ester, carbonate, oxygenated carbonate,oxacarbonate, pegylated carbonate, hydroxylated carbonate, branchedhydroxylated carbonate, aminoalkyl carbonate, cyclic aminoalkylcarbonate, acylated aminoalkyl carbonate, hydroxycarbonylalkylcarbonate, carbamate, alkyl carbamate, aminoalkyl carbamate, acylatedaminoalkyl carbamate, cyclic aminoalkyl carbamate, oxacarbamate,pegylated carbamate, hydroxylated carbamate, branched hydroxylatedcarbamate, hydroxycarbonylalkyl carbamate, dihydrogen phosphate, alkalimetal phosphate salt, alkaline earth metal phosphate salt, and phosphatesalt of organic base; and

-   -   (b) combining the selected Δ⁹-THC prodrug with a        pharmaceutically acceptable excipient to form a pharmaceutical        composition; and    -   (c) contacting the pharmaceutical composition with the skin of a        mammal.

A further embodiment described herein is a method of treating a medicalcondition in a mammal comprising the steps of administering a Δ⁹-THCprodrug selected from the group consisting of:

wherein R₁ is selected from ester, oxygenated ester, oxaester, pegylatedester, hydroxylated ester, branched hydroxylated ester, succinic acidmonoester, oxalic acid mixed pegylated ester, amino ester, cyclic aminoester, acylated amino ester, carbonate, oxygenated carbonate,oxacarbonate, pegylated carbonate, hydroxylated carbonate, branchedhydroxylated carbonate, aminoalkyl carbonate, cyclic aminoalkylcarbonate, acylated aminoalkyl carbonate, hydroxycarbonylalkylcarbonate, carbamate, alkyl carbamate, aminoalkyl carbamate, acylatedaminoalkyl carbamate, cyclic aminoalkyl carbamate, oxacarbamate,pegylated carbamate, hydroxylated carbamate, branched hydroxylatedcarbamate, hydroxycarbonylalkyl carbamate, dihydrogen phosphate, alkalimetal phosphate salt, alkaline earth metal phosphate salt, and phosphatesalt of organic base; and

In one embodiment, the resulting Δ⁹-THC prodrug of Formula I is morehydrophilic than Δ⁹-THC and therefore more water soluble. The log_(io)values of the water/octanol partition coefficient (log P) for Δ⁹-THC andvarious prodrugs of Δ⁹-THC are shown in FIG. 10. A further embodiment isa prodrug of Δ⁹-THC having a log P value less than that of Δ⁹-THC. Afurther embodiment is a prodrug of Δ⁹-THC having a log P value greaterthan that of Δ⁹-THC. A further embodiment is a prodrug of Δ⁹-THC havinga log P value which is approximately equal to that of Δ⁹-THC.

Pharmaceutical Excipients

The pharmaceutical compositions described herein can, if desired,include one or more pharmaceutically acceptable excipients. The term“excipient” herein means any substance, not itself a therapeutic agent,used as a carrier or vehicle for delivery of a therapeutic agent to asubject or added to a pharmaceutical composition, for example, toimprove its handling or storage properties or to permit or facilitateformation of a dose unit of the composition. Excipients include, by wayof illustration and not limitation, solvents, thickening agents,penetration enhancers, wetting agents, lubricants, emollients,substances added to mask or counteract a disagreeable odor, fragrances,and substances added to improve appearance or texture of thecomposition. Any such excipients can be used in any dosage forms ofaccording to the present disclosure. The foregoing list of excipients isnot meant to be exhaustive but merely illustrative as a person ofordinary skill in the art would recognize that additional excipientscould be used to achieve the desired goals for delivery of the Δ⁹-THCprodrug.

Compositions of the disclosure containing excipients can be prepared byany technique known to a person of ordinary skill in the art ofpharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine orother related discipline that comprises admixing an excipient with adrug or therapeutic agent.

In one embodiment, the Δ⁹-THC prodrugs described herein can be combinedwith a penetration enhancer. Non-limiting examples of penetrationenhancing agents include C8-C22 fatty acids such as isostearic acid,octanoic acid, and oleic acid; C8-C22 fatty alcohols such as oleylalcohol and lauryl alcohol; lower alkyl esters of C8-C22 fatty acidssuch as ethyl oleate, isopropyl myristate, butyl stearate, and methyllaurate; di(lower)alkyl esters of C6-C22 diacids such as diisopropyladipate; monoglycerides of C8-C22 fatty acids such as glycerylmonolaurate; tetrahydrofurfuryl alcohol polyethylene glycol ether;polyethylene glycol, propylene glycol; 2-(2-ethoxyethoxy)ethanol;diethylene glycol monomethyl ether; alkylaryl ethers of polyethyleneoxide; polyethylene oxide monomethyl ethers; polyethylene oxide dimethylethers; dimethyl sulfoxide; glycerol; ethyl acetate; acetoacetic ester;N-alkylpyrrolidone; and terpenes. Additional penetration enhancerssuitable for use can also be found in U.S. patent application Ser. No.10/032,163, published as US 2002-0111377 A1, on Aug. 15, 2002.

In one embodiment, the Δ⁹-THC prodrugs described herein can be combinedwith thickening agents (aka gelling agents). The thickening agent usedherein may include anionic polymers such as polyacrylic acid (CARBOPOL®by Noveon, Inc., Cleveland, Ohio), carboxypolymethylene,carboxymethylcellulose and the like, including derivatives of Carbopol®polymers, such as Carbopol® Ultrez 10, Carbopol® 940, Carbopol® 941,Carbopol® 954, Carbopol® 980, Carbopol® 981, Carbopol® ETD 2001,Carbopol® EZ-2 and Carbopol® EZ-3, and other polymers such as Pemulen®polymeric emulsifiers, and Noveon® polycarbophils. Additional thickeningagents, enhancers and adjuvants may generally be found in Remington'sThe Science and Practice of Pharmacy as well as the Handbook fPharmaceutical Excipients, Arthur H. Kibbe ed. 2000. Thickening agentsor gelling agents are present in an amount sufficient to provide thedesired rheological properties of the composition. Illustratively, oneor more pharmaceutically acceptable thickening agent or gelling agentare present in a total amount by weight of about 0.1%, about 0.25%,about 0.5%, about 0.75%, about 1%, about 1.25%, about 1.5%, about 1.75%,about 2.0%, about 2.25%, about 2.5%, about 2.75%, about 3.0%, about3.25%, about 3.5%, about 3.75%, about 4.0%, about 4.25%, about 4.5%,about 4.75%, about 5.0%, about 5.25%, about 5.5%, about 5.75%, about6.0%, about 6.25%, about 6.5%, about 6.75%, about 7.0%, about 7.25%,about 7.5%, about 7.75%, about 8.0%, about 8.25%, about 8.5%, about8.75%, about 9.0%, about 9.25%, about 9.5%, about 9.75%, about 10%,about 10.5%, about 11%, about 11.5%, about 12%, about 12.5%, about 13%,about 13.5%, about 14%, about 14.5% or about 15%.

In one embodiment a neutralizing agent is optionally present to assistin forming a gel. Suitable neutralizing agents include sodium hydroxide(e.g., as an aqueous mixture), potassium hydroxide (e.g., as an aqueousmixture), ammonium hydroxide (e.g., as an aqueous mixture),triethanolamine, tromethamine (2-amino 2-hydroxymethyl-1, 3propanediol), aminomethyl propanol (AMP), tetrahydroxypropyl ethylenediamine, diisopropanolamine, Ethomeen C-25 (Armac Industrial Division),Di-2 (ethylhexyl) amine (BASF-Wyandotte Corp., Intermediate ChemicalsDivision), triamylamine, Jeffamine D-1000 (Jefferson Chemical Co.),b-Dimethylaminopropionitrite (American Cyanamid Co.), Armeen CD (ArmacIndustrial Division), Alamine 7D (Henkel Corporation), dodecylamine andmorpholine. The neutralizing agent is present in an amount sufficient toform a gel which is suitable for contact with the skin of a mammal.

In one embodiment, the formulation is a gel, an ointment, a cream or apatch and comprises a Δ⁹-THC prodrug, optionally a penetration enhancingagent, a thickening agent, a lower alcohol, such as ethanol orisopropanol; and water. In another embodiment, the formulation is a gel,an ointment, a cream or a patch, further comprised of sodium hydroxideor triethanolamine or potassium hydroxide, or a combination thereof, inan amount sufficient, as is known in the art, to assist the gellingagent in forming a gel.

In one embodiment, a solution of sodium hydroxide is used, such as,e.g., 0.1 N sodium hydroxide solution, 0.2 N sodium hydroxide solution,0.5 N sodium hydroxide solution, 1.0 N sodium hydroxide solution, 1.5 Nsodium hydroxide solution, 2.0 N sodium hydroxide solution, or any othersuitable solution for providing an amount sufficient of the sodiumhydroxide to the composition. In one embodiment, the compositioncomprises about 1% to about 10% 0.1 N sodium hydroxide.

Additional embodiments include the following compositions:

Gel Formulation Used with Patches (18 mg/mL Δ⁹-THC or Δ⁹-THC Prodrug)

75.2% propylene glycol, USP 18.8% sterile water for injection, USP 6.0%diethylene glycol monoethyl ether (Transcutol HP), EP/USP/NF 5.0%hydroxyethylcellulose (Natrosol ®), NF based on weight of other threecomponents

Gel Formulation Used for Rubbing into Skin

72.5-67.5%      absolute ethanol, USP/NF 20.38-15.38%       sterilewater for injection, USP 4.72%  0.1N NaOH (NF) in sterile water forinjection, USP 1-10%  Δ⁹-THC or Δ⁹-THC prodrug 0.9% Carbopol 980 ®, NF0.5% isopropyl myristate, USP/NF

Gel Formulation

78.1% absolute ethanol, USP/NF 15.3% sterile water for injection, USP1.5% triethanolamine, NF 3.5% Δ⁹-THC or Δ⁹-THC prodrug 1.0% Carbopol980 ®, NF 0.6% isopropyl myristate, USP/NF

Gel Formulation

91.75-82.75%       absolute ethanol, USP/NF 5.0% propylene glycol, USP1-10%  Δ⁹-THC or Δ⁹-THC prodrug 1.25%  polyoxyethylene (15)cocoalkylamines (Ethomeen ® C/25) 0.5% Carbopol 980 ®, NF 0.5% isopropylmyristate, USP/NF

Compositions described herein optionally comprise one or morepharmaceutically acceptable wetting agents as excipients. Non-limitingexamples of surfactants that can be used as wetting agents incompositions of the disclosure include quaternary ammonium compounds,for example benzalkonium chloride, benzethonium chloride andcetylpyridinium chloride, dioctyl sodium sulfosuccinate, polyoxyethylenealkylphenyl ethers, for example nonoxynol 9, nonoxynol 10, and octoxynol9, poloxamers (polyoxyethylene and polyoxypropylene block copolymers),polyoxyethylene fatty acid glycerides and oils, for examplepolyoxyethylene (8) caprylic/capric mono- and diglycerides (e.g.,Labrasol™ of Gattefossé), polyoxyethylene (35) castor oil andpolyoxyethylene (40) hydrogenated castor oil; polyoxyethylene alkylethers, for example polyoxyethylene (20) cetostearyl ether,polyoxyethylene fatty acid esters, for example polyoxyethylene (40)stearate, polyoxyethylene sorbitan esters, for example polysorbate 20and polysorbate 80 (e.g., Tween™ 80 of ICI), propylene glycol fatty acidesters, for example propylene glycol laurate (e.g., Lauroglycol™ ofGattefossé), sodium lauryl sulfate, fatty acids and salts thereof, forexample oleic acid, sodium oleate and triethanolamine oleate, glycerylfatty acid esters, for example glyceryl monostearate, sorbitan esters,for example sorbitan monolaurate, sorbitan monooleate, sorbitanmonopalmitate and sorbitan monostearate, tyloxapol, and mixturesthereof. Such wetting agents, if present, constitute in total about0.25% to about 15%, about 0.4% to about 10%, or about 0.5% to about 5%,of the total weight of the composition. Illustratively, one or morepharmaceutically acceptable wetting agents are present in a total amountby weight of about 0.25%, about 0.5%, about 0.75%, about 1%, about1.25%, about 1.5%, about 1.75%, about 2.0%, about 2.25%, about 2.5%,about 2.75%, about 3.0%, about 3.25%, about 3.5%, about 3.75%, about4.0%, about 4.25%, about 4.5%, about 4.75%, about 5.0%, about 5.25%,about 5.5%, about 5.75%, about 6.0%, about 6.25%, about 6.5%, about6.75%, about 7.0%, about 7.25%, about 7.5%, about 7.75%, about 8.0%,about 8.25%, about 8.5%, about 8.75%, about 9.0%, about 9.25%, about9.5%, about 9.75% or about 10%.

Compositions described herein optionally comprise one or morepharmaceutically acceptable lubricants (including anti-adherents and/orglidants) as excipients. Suitable lubricants include, eitherindividually or in combination, glyceryl behapate (e.g., Compritol™888); stearic acid and salts thereof, including magnesium (magnesiumstearate), calcium and sodium stearates; hydrogenated vegetable oils(e.g., Sterotex™); colloidal silica; talc; waxes; boric acid; sodiumbenzoate; sodium acetate; sodium fumarate; sodium chloride; DL-leucine;PEG (e.g., Carbowax™ 4000 and Carbowax™ 6000); sodium oleate; sodiumlauryl sulfate; and magnesium lauryl sulfate. Such lubricants, ifpresent, constitute in total about 0.1% to about 10%, about 0.2% toabout 8%, or about 0.25% to about 5%, of the total weight of thecomposition. Illustratively, one or more pharmaceutically acceptablelubricants are present in a total amount by weight of about 0.1%, about0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about0.8%, about 0.9%, about 1.0%, about 1.1%, about 1.2%, about 1.3%, about1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, about2.0%, about 2.1%, about 2.2%, about 2.3%, about 2.4%, about 2.5%, about2.6%, about 2.7%, about 2.8%, about 2.9%, about 3.0%, about 3.1%, about3.2%, about 3.3%, about 3.4%, about 3.5%, about 3.6%, about 3.7%, about3.8%, about 3.9%, about 4.0%, about 4.1%, about 4.2%, about 4.3%, about4.4%, about 4.5%, about 4.6%, about 4.7%, about 4.8%, about 4.9%, about5.0%, about 5.1%, about 5.2%, about 5.3%, about 5.4%, about 5.5%, about5.6%, about 5.7%, about 5.8%, about 5.9%, about 6.0%, about 6.1%, about6.2%, about 6.3%, about 6.4%, about 6.5%, about 6.6%, about 6.7%, about6.8%, about 6.9%, about 7.0%, about 7.1%, about 7.2%, about 7.3%, about7.4%, about 7.5%, about 7.6%, about 7.7%, about 7.8%, about 7.9%, about8.0%, about 8.1%, about 8.2%, about 8.3%, about 8.4%, about 8.5%, about8.6%, about 8.7%, about 8.8%, about 8.9%, about 9.0%, about 9.1%, about9.2%, about 9.3%, about 9.4%, about 9.5%, about 9.6%, about 9.7%, about9.8%, about 9.9% or about 10.0%.

In another embodiment, the compositions described herein optionallycomprise an emollient. Illustrative emollients include mineral oil,mixtures of mineral oil and lanolin alcohols, cetyl alcohol, cetostearylalcohol, petrolatum, petrolatum and lanolin alcohols, cetyl esters wax,cholesterol, glycerin, glyceryl monostearate, isopropyl myristate,isopropyl palmitate, lecithin, allyl caproate, althea officinalisextract, arachidyl alcohol, argobase EUC, butylene glycoldicaprylate/dicaprate, acacia, allantoin, carrageenan, cetyldimethicone, cyclomethicone, diethyl succinate, dihydroabietyl behenate,dioctyl adipate, ethyl laurate, ethyl palmitate, ethyl stearate, isoamyllaurate, octanoate, PEG-75 lanolin, sorbitan laurate, walnut oil, wheatgerm oil super refined almond, super refined sesame, super refinedsoybean, octyl palmitate, caprylic/capric triglyceride and glycerylcocoate. An emollient, if present, is present in the compositionsdescribed herein in an amount of about 1% to about 30%, about 3% toabout 25%, or about 5% to about 15%, by weight. Illustratively, one ormore emollients are present in a total amount of about 1%, about 2%,about 3%, about 4%, about 5%, about 6%, about 7%, about 8%, about 9%,about 10%, about 11%, about 12%, about 13%, about 14%, about 15%, about16%, about 17%, about 18%, about 19%, about 20%, about 21%, about 22%,about 23%, about 24%, about 25%, about 26%, about 27%, about 28%, about29%, or about 30%, by weight.

In one embodiment, a composition comprises an antimicrobialpreservative. Illustrative anti-microbial preservatives include acids,including but not limited to benzoic acid, phenolic acid, sorbic acids,alcohols, benzethonium chloride, bronopol, butylparaben, cetrimide,chlorhexidine, chlorobutanol, chlorocresol, cresol, ethylparaben,imidurea, methylparaben, phenol, phenoxyethanol, phenylethyl alcohol,phenylmercuric acetate, phenylmercuric borate, phenylmercuric nitrate,potassium sorbate, propylparaben, sodium propionate, or thimerosal. Theanti-microbial preservative, if present, is present in an amount ofabout 0.1% to about 5%, about 0.2% to about 3%, or about 0.3% to about2%, by weight, for example about 0.2%, 0.4%, 0.6%, 0.8%, 1%, 1.2%, 1.4%,1.6%, 1.8%, 2%, 2.2%, 2.4%, 2.6%. 2.8%, 3.0%, 3.2%, 3.4%, 3.6%, 3.8%,4%, 4.2%, 4.4%, 4.6%, 4.8%, or 5%.

Compositions described herein optionally compromise one or moreemulsifying agents. The term “emulsifying agent” refers to an agentcapable of lowering surface tension between a non-polar and polar phaseand includes compounds defined elsewhere as “self emulsifying” agents.Suitable emulsifying agents can come from any class of pharmaceuticallyacceptable emulsifying agents including carbohydrates, proteins, highmolecular weight alcohols, wetting agents, waxes and finely dividedsolids. The optional emulsifying agent, if present, is present in acomposition in a total amount of about 1% to about 15%, about 1% toabout 12%, about 1% to about 10%, or about 1% to about 5% by weight ofthe composition. Illustratively, one or more emulsifying agents arepresent in a total amount by weight of about 1%, about 2%, about 3%,about 4%, about 5%, about 6%, about 7%, about 8%, about 9%, about 10%,about 11%, about 12%, about 13%, about 14%, or about 15%.

In another embodiment, the water immiscible solvent comprises propyleneglycol, and is present in a composition in an amount of about 1% toabout 99%, by weight of the composition, for example about 1%, about 5%,about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about40%, about 45%, about 50%, about 55%, about 60%, about 65%, about 70%,about 75%, about 80%, about 85%, about 90%, about 95% or about 99%.

Compositions described herein may optionally comprise one or morebinding agents. Binding agents may be either dry or wet. Dry bindingagents may include simple and complex carbohydrates (e.g., sucrose,glucose, fructose, maltose, lactose, maltodextrins, starch, modifiedstarches, mannitol, sorbitol, maltitol, xylitol, and erthritol),cellulose, and cellulosic derivatives (e.g., microcrystalline cellulose,carboxymethyl cellulose, and hydroxyethyl cellulose). Wet binder agentsmay include polyvinyl pyrrolidone, methylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, carboxymethylcellulose,xanthan gum, carrageenan gum, locust bean gum, alginates, and acacia.Depending on the desired result, a person of ordinary skill in the artof pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine orother related discipline that comprises admixing an excipient with adrug or therapeutic agent to a composition would be able to select theappropriate binding agent and the relative concentration of the bindingagent.

In another embodiment, the compositions described herein may containdisintegrants, such as sodium starch glycolate, crosspovidone,crosscarmellose, microcrystalline cellulose and starch. Depending on thedesired result, a person of ordinary skill in the art of pharmacy,pharmaceutics, drug delivery, pharmacokinetics, medicine or otherrelated discipline that comprises admixing an excipient with a drug ortherapeutic agent to a composition would be able to select theappropriate disintegrant and the relative concentration of thedisintegrant.

In a further embodiment, the compositions disclosed herein may containlubricants, such as magnesium stearate, stearic acid and itspharmaceutically acceptable salts, talc, vegetable oils, and waxes.Depending on the desired result, a person of ordinary skill in the artof pharmacy, pharmaceutics, drug delivery, pharmacokinetics, medicine orother related discipline that comprises admixing an excipient with adrug or therapeutic agent to a composition would be able to select theappropriate lubricant and the relative concentration of the lubricant.

Compositions described herein may also optionally comprise one or moretaste enhancers, such as sweeteners, including aspartame, acesulfamepotassium, sucralose and saccharin or taste masking agents, such asflavorings. Depending on the desired result, a person of ordinary skillin the art of pharmacy, pharmaceutics, drug delivery, pharmacokinetics,medicine or other related discipline that comprises admixing anexcipient with a drug or therapeutic agent to a composition would beable to select the appropriate taste enhancer or taste making agent andthe relative concentration of the taste enhancer or taste masking agent.

Therapeutic Uses

In one embodiment, compositions disclosed herein comprise one or moreΔ⁹-THC prodrugs in a total amount of between about 0.1% and about 95% byweight of the composition, for example about 0.1%, about 0.2%, about0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about0.9%, about 1%, about 2%, about 3%, about 4%, about 5%, about 6%, about7%, about 8%, about 9%, about 10%, about 15%, about 20%, about 25%,about 30%, about 35%, about 40%, about 45%, about 50%, about 55%, about60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90% orabout 95%.

The term “therapeutically effective amount” or “therapeutically and/orprophylactically effective amount” as used herein refers to an amount ofcompound or agent that is sufficient to elicit the required or desiredtherapeutic and/or prophylactic response, as the particular treatmentcontext may require.

It will be understood that a therapeutically and/or prophylacticallyeffective amount of a drug for a subject is dependent inter alia on thebody weight of the subject as well as other factors known to a person ofordinary skill in the art. A “subject” herein to which a therapeuticagent or composition thereof can be administered includes mammals suchas a human subject of either sex and of any age, and also includes anynonhuman animal, particularly a domestic or companion animal,illustratively a cat, dog or a horse as well as laboratory animals suchas guinea pigs.

The terms “treat”, “treated”, “treating” and “treatment” are to bebroadly understood as referring to any response to, or anticipation of,a medical condition in a mammal, particularly a human, and includes butis not limited to:

-   -   (i) preventing the medical condition from occurring in a        subject, which may or may not be predisposed to the condition,        but has not yet been diagnosed with the condition and,        accordingly, the treatment constitutes prophylactic treatment        for the medical condition;    -   (ii) inhibiting the medical condition, i.e., arresting, slowing        or delaying the onset, development or progression of the medical        condition; or    -   (iii) relieving the medical condition, i.e., causing regression        of the medical condition.

In one embodiment, a therapeutically effective amount of a Δ⁹-THCprodrug is administered to treat a medical condition selected from thegroup consisting of: anorexia, nausea, emesis, pain, wasting syndrome,HIV-wasting, chemotherapy induced nausea and vomiting, alcohol usedisorders, anti-tumor, amyotrophic lateral sclerosis, glioblastomamultiforme, glioma, increased intraocular pressure, glaucoma, cannabisuse disorders, Tourette's syndrome, dystonia, multiple sclerosis,inflammatory bowel disorders, arthritis, dermatitis, Rheumatoidarthritis, systemic lupus erythematosus, anti-inflammatory,anti-convulsant, anti-psychotic, anti-oxidant, neuroprotective,anti-cancer, immunomodulatory effects, peripheral neuropathic pain,neuropathic pain associated with post-herpetic neuralgia, diabeticneuropathy, shingles, burns, actinic keratosis, oral cavity sores andulcers, post-episiotomy pain, psoriasis, pruritis, contact dermatitis,eczema, bullous dermatitis herpetiformis, exfoliative dermatitis,mycosis fungoides, pemphigus, severe erythema multiforme (e.g.,Stevens-Johnson syndrome), seborrheic dermatitis, ankylosingspondylitis, psoriatic arthritis, Reiter's syndrome, gout,chondrocalcinosis, joint pain secondary to dysmenorrhea, fibromyalgia,musculoskeletal pain, neuropathic-postoperative complications,polymyositis, acute nonspecific tenosynovitis, bursitis, epicondylitis,post-traumatic osteoarthritis, synovitis, and juvenile rheumatoidarthritis.

Pharmaceutical Dosage Forms

In one embodiment, a single dosage unit of any formulation comprises atherapeutically effective amount or a therapeutically and/orprophylactically effective amount of a Δ⁹-THC prodrug.

In one embodiment, compositions described herein are suitable fortransdermal administration. In another embodiment, transdermallyadministrable compositions are adapted for administration in and/oraround the abdomen, back, chest, legs, arms, scalp or other suitableskin surface and may include formulations in which the Δ⁹-THC prodrug isadministered in patches, ointments, creams, suspensions, lotions,pastes, gels, sprays, foams or oils.

In another embodiment, compositions described herein which aretransdermally administrable include formulations in which the Δ⁹-THCprodrug is placed in a glycol or gel formulation.

In one embodiment, compositions described herein are suitable fortopical administration. In another embodiment, topical administrablecompositions are adapted for administration in and/or around theabdomen, back, chest, legs, arms, scalp or other suitable skin surfaceand may include formulations in which the Δ⁹-THC prodrug is administeredin patches, ointments, creams, suspensions, lotions, pastes, gels,sprays, foams or oils.

In another embodiment, the compositions described herein are suitablefor oral administration. In another embodiment, compositions describedherein that are orally administrable include formulations in which theΔ⁹-THC prodrug is administered in tablets, capsules, suspensions, syrupsor liquids. In an additional embodiment, the composition maybeformulated as extended release or long acting tablet or capsule. In afurther embodiment, the oral dosage form may be enteric coated usingcompositions and techniques known to a person of ordinary skill in theart.

In one embodiment, compositions described herein are suitable for buccaladministration. In another embodiment, compositions described hereinthat are bucally administrable may include formulations in which theΔ⁹-THC prodrug is administered in lozenges, sprays, gels, pastes,dissolvable tablets or dissolvable strips.

In one embodiment, compositions described herein are suitable forsublingual administration. In another embodiment, compositions describedherein that are sublingually administrable may include formulations inwhich the Δ⁹-THC prodrug is administered in lozenges, sprays, gels,pastes, dissolvable tablets or dissolvable strips.

In one embodiment, compositions described herein are suitable forinjectable administration. In another embodiment, compositions describedherein that are injectably administrable may include formulations inwhich the Δ⁹-THC prodrug is administered as an intravenous, intrathecal,subcutaneous or depot injection.

In one embodiment, compositions described herein are suitable for rectaladministration. In another embodiment, compositions described hereinthat are rectally administrable may include formulations in which theΔ⁹-THC prodrug is placed in suppositories, ointments, creams,suspensions, solutions, lotions, pastes, gels, sprays, foams or oils.

In one embodiment, compositions described herein are suitable forvaginal administration. In another embodiment, compositions describedherein that are vaginally administrable may include formulations inwhich the Δ⁹-THC prodrug is placed in suppositories, ointments, creams,suspensions, solutions, lotions, pastes, gels, sprays, foams or oils.

In one embodiment, compositions described herein are suitable for ocularadministration. In another embodiment, compositions described hereinthat are ocularly administrable may include formulations in which theΔ⁹-THC prodrug is placed in ointments, suspensions, solutions, gels orsprays.

In one embodiment, compositions described herein are suitable for nasaladministration. In another embodiment, compositions described hereinthat are nasally administrable may include formulations in which theΔ⁹-THC prodrug is placed in ointments, suspensions, solutions, lotions,pastes, gels, sprays or mists.

EXAMPLES Example 1

Section I. Summary

The objective was to synthesize Δ⁹-tetrahydrocannabinol prodrugs andassess the permeation of Δ⁹-tetrahydrocannabinol and its prodrugsthrough human abdominal skin in vitro. Nine Δ⁹-tetrahydrocannabinolprodrugs were synthesized and tested. Synthesized prodrugs ofΔ⁹-tetrahydrocannabinol were analyzed for chemical stability in aformulation comparable to donor solution for diffusion testing to screenpotential candidates' chemical stability and to decide the capability ofthe prodrug to withstand the formulation during the course of adiffusion study. Synthesized prodrugs of Δ⁹-tetrahydrocannabinol wereanalyzed for plasma stability to monitor the rate of conversion toΔ⁹-tetrahydrocannabinol. Potential candidates would convert readily toΔ⁹-tetrahydrocannabinol in plasma whereas stable prodrugs would convertvery little. The procedure was performed to screen out compounds with nobioconversion to the parent molecule. Flow through diffusion cells wereused for the permeation studies. The receiver used for the permeationstudies was either 25% aqueous ethanol or 40% aqueous PEG (polyethyleneglycol) 400. Donor solution was comprised of 100% PG (propylene glycol),1:1:1 PG:ethanol:H₂O, 2.36:1.18:1 PG:ethanol:H₂O, or a rubbed in gelformulation. The flux and lag time values of Δ⁹-tetrahydrocannabinol andΔ⁹-tetrahydrocannabinol prodrugs were obtained from the permeationprofiles. Drug accumulation in the skin after a 24 h diffusionexperiment was determined as μmol/g wet tissue weight.

Section II. Methodology

1.0 Purpose: Synthesize Δ⁹-tetrahydrocannabinol prodrugs and assess thehuman skin permeation of Δ⁹-tetrahydrocannabinol andΔ⁹-tetrahydrocannabinol prodrugs in vitro. The following compounds weresynthesized and assessed:

2.0 Skin Details

The skin samples used in the following experiments were obtained fromabdominal reduction surgery and dermatomed to a thickness ofapproximately 200 μm. The skin samples used herein were frozen at −20°C. for less than six months.

3.0 Chemicals

Acetonitrile (HPLC grade), trifluoroacetic acid, triethylamine,gentamicin sulfate, isopropyl myristate (IPM), acetone,4-dimethylaminopyridine, tetraethyleneglycol monomethyl ether,1-octanethiol, and sodium hydroxide were purchased through FisherScientific (Fairlawn, N.J.). Methanol (HPLC grade), acetonitrile (HPLCgrade), N,N′-dicyclohexylcarbodiimide, N,N-dimethylglycine,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), mono-Fmoc-1,4-butanediaminehydrochloride, and polyethylene glycol 400 (PEG 400) were purchasedthrough VWR (West Chester, Pa.). Propylene glycol (PG), triethyleneglycol, triphosgene, Δ⁹-tetrahydrocannabinol, and absolute ethanol,thiphenol, succinic anhydride, N-formylglycine,N-(2-nitrophenylsulfenyl)-L-proline dicyclohexylammonium salt werepurchased from Sigma-Aldrich (St. Louis, Mo.). Petroleum ether, ethylacetate, hexane, chloroform, anhydrous sodium sulfate, methylenechloride, and dichloromethane were obtained from the University ofKentucky Chemical Stores (Lexington, Ky.). Argon and pre-purifiednitrogen were purchased from Scott Gross Company (Lexington, Ky.).Carbopol® 980 was obtained from Noveon, Inc. (Cleveland, Ohio). Nanopurewater was obtained from a Barnstead NANOpure® Diamond™ Ultrapure waterfiltration system (Dubuque, Iowa). The following compounds weresynthesized according to literature procedures:3,6,9,12-tetraoxatridecanoic acid (Macromolecules, 39 (12), 3978 -3979,2006.) and N-formylsarcosine (U.S. Pat. No. 5,684,161 (1997).

4.0 Synthesis of Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) Prodrugs

4.1 Synthesis of ALL00117 (Δ⁹-Tetrahydrocannabinol3,6,9,12-tetraoxatridecanoyl ester).

THC (68.6 mg, 0.218 mmol) was dissolved in 5 mL of dichloromethane.Next, 3,6,9,12-tetraoxatridecanoic acid (63.0 mg, 0.283 mmol) indichloromethane (1 mL) was added followed by 4-dimethylaminopyridine(4.5 mg, 0.0218 mmol) and N,N′-dicyclohexylcarbodiimide (76.5 mg, 0.371mmol). The mixture was stirred at ambient temperature for 2 h. Themixture was diluted with hexane (6 mL), filtered, concentrated under areduced pressure and chromatographed on silica gel with hexane-ethylacetate (gradient 4:1, 2:1, 1:1, 0:1). Fractions containing the productwere concentrated under a reduced pressure, dissolved in hexane with afew drops of ethyl acetate, filtered and concentrated again to affordALL00117 (83 mg, 73%) as an oil.

For ALL00117, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ=6.57(1H, d,J=1.8, H−4); 6.42(1H, d, J=1.8, H−2); 5.86-6.90 (1H, m, H−10); 4.42(2H,s, OCH₂CO₂); 3.88-3.76(2H, m, PEG); 3.75-3.64(8H, m, PEG); 3.58-3.54(2H,m, PEG); 3.39(s, 3H, CH₂OCH ₃); 3.11-3.03(1H, m, H−10a); 2.49(2H, t,J=8.3, ArCH₂); 2.09-2.17(2H, m); 1.85-1.94 (1H, m); 1.62-1.70(4H, m);1.52-1.62(2H, m); 1.41(3H, s, 6β-Me); 1.24-1.41(5H, m); 1.09(3H, s,6α-Me); 0.88 (3H, t, J=7.0, CH₂ CH₃ ).

4.2 Synthesis of ALL00118 (Δ⁹-Tetrahydrocannabinol N,N-dimethylglycylester).

The same procedure as for ALL00117 starting from N,N-dimethylglycine(60.3 mg, 0.585 mmol), THC (141 mg, 0.45 mmol),N,N′-dicyclohexylcarbodiimide (158 mg, 0.765 mmol),4-dimethylaminopyridine (9.3 mg, 0.045 mmol) in dichloromethane (4.5 mL)afforded 143 mg (80%) of ALL00118 as an oil.

For ALL00118, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ=6.55(1H, d,J=1.8, H−4); 6.41(1H, d, J=1.8, H−2); 5.89-5.92 (1H, m, H−10); 3.43(2H,s, COCH₂); 3.04-3.12 (1H, m, H−10a); 2.49(2H, t, J=7.8, ArCH₂); 2.44(6H,s, _(N)(_(CH3))₂)_(;) 2.09-2.16(2H, m); 1.85-1.93 (1H, m); 1.62-1.70(4H,m); 1.52-1.61(2H, m); 1.40(3H, s, 6β-Me); 1.23-1.40(5H, m); 1.08(3H, s,6α-Me); 0.88 (3H, t, J=7.0, CH₂ CH₃ ).

4.3 Synthesis of ALL00119 (Δ⁹-Tetrahydrocannabinol3,6,9,12-tetraoxatridecyl carbonate).

Tetraethyleneglycol monomethyl ether (208 mg, 0.00065 mol) was dissolvedin dichloromethane and the solution chilled in an ice bath. Triphosgene(56 mg, 0.00019 mol) was dissolved in dichloromethane and this solutionslowly added to the tetraethyleneglycol monomethyl ether solution withstirring while maintained at 0° C. The mixture was kept under argon andstirred for three hours.

Tetrahydrocannabinol (170 mg, 0.00054 mol) was dissolved in 10 mL ofdichloromethane. Triethylamine (82 mg, 0.00081 mol) was addeddrop-by-drop. The solution was covered with argon, sealed and stirredfor three hours.

The two solutions were combined and allowed to come to ambienttemperature. The mixture was kept under argon and allowed to stirovernight. The solvent was reduced to a small volume under nitrogen andhexane was added. The precipitate that formed was removed by filtration.The filtrate was taken to dryness under vacuum. The crude product wasreconstituted in 1:1 hexane: methylene chloride.

A silica column was used to purify the crude material using 1:1 hexane:ethyl acetate as an eluent to afford 112 mg (38%) of ALL00119. Thepurified product appeared as a transparent, viscous oil with light ambercolor.

For ALL00119, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.56(1H, d,J=1.8, H−4); 6.50(1H, d, J=1.8, H−2); 5.98-6.02 (1H, m, H−10);4.36-4.42(2H, m, COOCH₂); 3.79(2H, t, J=4.7, CH₂ OCH₃); 3.63-3.71(10H,m); 3.54-3.57(2H, m); 3.38(3H, s, CH₂OCH₃ ); 3.13-3.21 (1H, m, H−10a);2.49(2H, t, J=7.8, ArCH₂); 2.10-2.17(2H, m); 1.86-1.94 (1H, m);1.63-1.71(4H, m); 1.52-1.62(2H, m); 1.41(3H, s, 6β-Me); 1.23-1.41(5H,m); 1.09(3H, s, 6α-Me); 0.88 (3H, t, J=7.0, CH₂ CH₃ ).

4.4 Synthesis of ALL00120 (Δ⁹-Tetrahydrocannabinol N-formylglycylester).

Tetrahydrocannabinol (134 mg, 0.00043 mol), N-formylglycine (56 mg,0.00054 mol), DMAP (5.3 mg, 0.00004 mol) were combined in 10 mLdichloromethane. The solution was stirred for 20 minutes at ambienttemperature. DCC (124 mg, 0.00060 mol) was added to the mixture. Themixture was allowed to stir overnight at ambient temperature.

The solution was reduced to a small volume under nitrogen and hexane wasadded. The precipitate that formed was removed by filtration. Thefiltrate was taken to dryness under vacuum. The crude product wasreconstituted in 1:1 hexane:methylene chloride.

A silica column was used to purify the crude material using 1:1 hexane:ethyl acetate as an eluent. The purified product appeared as atransparent, viscous oil with light amber color (136.8 mg, 80%).

For ALL00120, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ=8.29-8.31(1H, m, CHO); 6.58(1H, d, J=1.8, H−4); 6.43(1H, d, J=1.8, H−2); 6.15(1H, s br, NH); 5.85-5.88 (1H, m, H−10); 4.37(2H, AB system split by twoadditional coupling constants J=0.7 and J=5.1, OCOCH₂N); 2.99-3.06 (1H,m, H−10a); 2.50(2H, t, J=7.8, ArCH₂); 2.11-2.18(2H, m); 1.86-1.94 (1H,m); 1.62-1.70(4H, m); 1.52-1.62(2H, m); 1.41(3H, s, 6β-Me);1.23-1.40(5H, m); 1.08(3H, s, 6α-Me); 0.88 (3H, t, J=7.0, CH₂ CH₃ ).

4.5 Synthesis of ALL00121 (Δ⁹-Tetrahydrocannabinol N-formylsarcosylester).

The same procedure as for ALL00117 (reaction time 3h), starting fromN-formylsarcosine (73.2 mg, 0.625 mmol), THC (157 mg, 0.5 mmol),N,N′-dicyclohexylcarbodiimide (144.4 mg, 0.70 mmol) and4-dimethylaminopyridine (10.3 mg, 0.05 mmol) in dichloromethane (7.5 mL)afforded 161 mg (78%) of ALL00121 as an oil.

For ALL00121, the ¹H NMR (400 MHz, CDCl₃) was as follows: (the spectrumshows a mixture (˜2:1) of two rotamers), δ=(major rotamer) 8.16 (1H, s,CHO); 6.56(1H, d, J=1.6, H−4); 6.44(1H, d, J=1.8, H−2); 5.87-5.91 (1H,m, H−10); 4.36(2H, AB system, OCOCH₂N); 3.11(3H, s, NCH₃); 2.99-3.10(1H, m, H−10a); 2.49(2H, t, J=7.8, ArCH₂); 2.11-2.18(2H, m); 1.86-1.95(1H, m); 1.62-1.71(4H, m); 1.52-1.62(2H, m); 1.41(3H, s, 6β-Me);1.23-1.40(5H, m); 1.08(3H, s, 6α-Me); 0.88 (3H, t, J=7.0, CH₂ CH₃ ).

4.6 Synthesis of ALL00122 (Δ⁹-Tetrahydrocannabinol3,6,9,12-tetraoxatridecyl oxalate).

Tetraethyleneglycol monomethyl ether (402 mg, 1.93 mmol) was addeddropwise to oxalyl chloride (1.63 mL, 19.3 mmol) with stirring andcooling with ice-water. The mixture was allowed to warm to ambienttemperature, stirred for 20 min and concentrated under a reducedpressure. Benzene (0.3 mL) was added and the mixture was concentratedagain to afford 571 mg of a crude oxalic acidmono-3,6,9,12-tetraoxatridecyl ester chloride.

The crude oxalic acid mono-3,6,9,12-tetraoxatridecyl ester chloride (269mg, 0.90 mmol) was added dropwise to a solution of THC (188.6 mg, 0.60mmol) and 4-dimethylaminopyridine (223 mg, 1.08 mmol) in drydichloromethane (3 mL) under an argon atmosphere with stirring andcooling with ice-water. The mixture was stirred at ambient temperaturefor 2 h and additional two portions of both 4-dimethylaminopyridine (44mg) and the crude oxalic acid monoester chloride (54 mg) every 2 h withcooling. The mixture was stirred overnight, diluted with hexane,filtered and concentrated under a reduced pressure. The residue waschromatographed on silica gel with hexane-ethyl acetate (gradient 2:1,1:1, 0:1) to afford 189 mg (39%) of ALL00122 as an oil.

For ALL00122, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.60(1H, d,J=1.6, H−4); 6.49(1H, d, J=1.8, H−2); 5.99-6.03 (1H, m, H−10);4.46-4.57(2H, m, COOCH₂); 3.84(2H, t, J=4.9, CH₂OCH₃); 3.62-3.72(10H,m); 3.52-3.56(2H, m); 3.37(3H, s, CH₂OCH ₃); 3.04-3.12 (1H, m, H−10a);2.50(2H, t, J=7.8, ArCH₂); 2.09-2.16(2H, m); 1.85-1.93 (1H, m);1.63-1.71(4H, m); 1.52-1.61(2H, m); 1.41(3H, s, 6β-Me); 1.23-1.41(5H,m); 1.09(3H, s, 6α-Me); 0.88 (3H, t, J=6.9, CH₂ CH₃ ).

4.7 Synthesis of ALL00123 (Δ⁹-Tetrahydrocannabinol hemisuccinate).

A mixture of THC (204.4 mg, 0.65 mmol), succinic anhydride (91.1 mg,0.91 mmol) and 4-dimethylaminopyridine (187.8 mg, 0.91 mmol) indichloromethane (3.25 mL) was stirred at ambient temperature for 4 h. Anadditional amount of succinic anhydride (43 mg) and4-dimethylaminopyridine (102 mg) was added and the stirring wascontinued overnight. Glacial acetic acid (351 mg, 5.85 mmol) was addedwith stirring and the reaction mixture was directly chromatographed onsilica gel with hexane-ethyl acetate (gradient 2:1, 1:1, 0:1) to afford133.8 mg (50%) of ALL00123 as an oil.

For ALL00123, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.55(1H, d,J=1.8, H−4); 6.41(1H, d, J=1.8, H−2); 5.92-6.95 (1H, m, H−10); 3.01-3.08(1H, m, H−10a); 2.84-2.97 (2H, m, CH₂CH₂CO2H); 2.77-2.83(2H, m,CH₂CH₂CO2H); 2.49(2H, t, J=7.8, ArCH₂); 2.10-2.17(2H, m); 1.85-1.93 (1H,m); 1.62-1.70(4H, m); 1.52-1.61(2H, m); 1.40(3H, s, 6β-Me);1.25-1.40(5H, m); 1.08(3H, s, 6α-Me); 0.88 (3H, t, J=7.0, CH₂ CH ₃).

4.8 Synthesis of ALL00124 (Δ⁹-Tetrahydrocannabinol 4-aminobutylcarbamate).

To a stirred solution of mono-Fmoc-1,4-butanediamine hydrochloride (461mg, 1.33 mmol) in saturated NaHCO₃ aqueous solution (33.3 mL) anddichloromethane (22.2 mL) was added triphosgene (592 mg, 2.0 mmol) indichloromethane (5 mL) at ambient temperature. After stirring for 1 hr,the product was extracted with dichloromethane (40 mL), and thedichloromethane layer was dried over anhydrous Na₂SO₄, and concentrated.The residue was dissolved in ethyl acetate and the product wasprecipitated with addition of hexane. Fmoc-4-aminobutyl isocyanate wascollected by filtration as a white solid (305 mg, 68%).

Triethylamine was added to a solution of THC (141.5 mg, 0.45 mmol) indry DCM (0.4 mL). After stirring for 5 min at ambient temperature underan argon atmosphere, Fmoc-4-aminobutyl isocyanate solution in dry DCM(0.4 mL) was added and the stirring was continued overnight. Thereaction mixture was filtered and the filtrate was chromatographed onsilica gel with hexane-ethyl acetate (gradient 10:1, 5:1, 4:1, 2:1) toafford 216 mg (74%) of THC Fmoc-4-aminobutyl carbamate.

To a stirred solution of THC Fmoc-4-aminobutyl carbamate (202 mg, 0.31mmol) in THF (3 mL) was added 1-octanethiol (227 mg, 1.55 mml), followedby DBU (6.28 mg, 0.062 mmol). After stirring at ambient temperature for105 min the reaction mixture was diluted with hexane (3 mL) and directlychromatographed on silica gel with dichloromethane-methanol (gradient1:0, 20:1, 10:1, 5:1, 3:1, 2:1,1:1) to afford 120 mg (90%) of ALL00124as an oil. The compound should be stored at −20° C. immediately afterconcentration in order to avoid the decomposition to THC.

For ALL00124, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ=6.52(1H, d,J=1.6, H−4); 6.47(1H, d, J=1.6, H−2); 5.96-6.01 (1H, m, H−10); 5.44(1H,br t, J=5.6, OCONH); 3.24-3.34(2H, m); 3.15-3.24(2H, m); 3.09-3.15 (1H,m, H−10a); 2.75(2H, t, J=6.6); 2.48(2H, t, J=7.8, ArCH₂); 2.20-2.32(1H,m); 2.09-2.18(2H, m); 1.48-1.94(21H, m); 1.42(3H, s, 6β-Me);1.23-1.42(5H, m); 1.09(3H, s, 6α-Me); 0.87 (3H, t, J=7.0, CH₂ CH ₃).

4.9 Synthesis of ALL00125 (Δ⁹-Tetrahydrocannabinol prolyl ester).

N-(2-Nitrophenylsulfenyl)-L-proline was set free from itsdicyclohexylammonium salt (150 mg) by extraction from pH 3.5 citratebuffer with dichloromethane.

The same procedure as for ALL00117 (reaction time 1 h), starting fromN-(2-Nitrophenylsulfenyl)-L-proline, THC (76.8 mg, 0.244 mmol),N,N′-dicyclohexylcarbodiimide (70.4 mg, 0.34 mmol),4-dimethylaminopyridine (3 mg, 0.024 mmol) in dichloromethane afforded102.7 mg (74.5%) of THC N-Fmoc-prolyl ester as a yellow oil.

THC N-Fmoc-prolyl ester (99.7 mg) was dissolved in dry dichloromethanecontaining 10% (v/v) of thiophenol and 1.5% (v/v) of TFA. After 15 minthe mixture was poured into cold saturated sodium bicarbonate andextracted with dichloromethane (2×30 mL). The combined organic layerswere washed with cold water (30 mL), dried over anhydrous sodiumsulfate, and concentrated to approximately 2 mL.

The solution of the crude product was chromatographed on silica gel withdichloromethane-methanol (gradient 100:0, 100:1, 50:1, 40:1, 30:1). Thecombined fractions containing the product were diluted with chloroform,concentrated at 25° C. to about 10 mL, diluted with chloroform andconcentrated again to about 1 mL. The solution of the product wasdiluted with chloroform again (about 20 mL) and concentrated to dryness.The remaining oil was immediately dissolved in 1 mL of chloroform,concentrated to dryness, and immediately dissolved in 2 mL of chloroformto afford a stock solution of ALL00125 (about 30 mg/mL) that was storedat −20° C. Samples required for data collection were prepared byconcentrating the stock solution immediately before the experiments.

For ALL00125, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.56(1H, d,J=1.6, H−4); 6.41(1H, d, J=1.6, H−2); 5.92-5.95 (1H, m, H−10); 4.03(1H,br t, J=6.7); 3.10-3.21 (1H, m, H−10a); 2.93-3.09(2H, m); 2.49(2H, t,J=7.6, ArCH₂); 2.20-2.32(1H, m); 2.04-2.18(3H, m); 1.75-1.95(6H, m);1.63-1.71(4H, m); 1.52-1.62(2H, m); 1.41(3H, s, 6β-Me); 1.23-1.41(5H,m); 1.09(3H, s, 6α-Me); 0.88 (3H, t, J=7.0, CH₂ CH₃ ).

5.0 Plasma Stability Studies

Approximately 1 mg/mL of stock solution of each prodrug was prepared in100 μL of ethanol and 900 μL of acetonitrile. Next, 10 μL of stock wasspiked into 1 mL of plasma and vortexed. The samples were kept sealed inan amber vial and samples were obtained to analyze for bioconversion toparent drug.

6.0 In Vitro Skin Permeation Studies

6.1 Preparation of Receiver Fluid

Initially 25% aqueous ethanol was used for the receiver fluid but theprofiles were not typical and did not have enough time points to obtaina linear drug profile. A comparison between the 25% aqueous ethanol and40% aqueous PEG 400 receiver fluids was examined. The 40% PEG 400 gavethe typical profile and had higher concentrations of the respective drugso it was the receiver fluid used for the remainder of the diffusionstudies. The receiver fluid was prepared by measuring 900 mL of nanopureH₂O into a graduated cylinder. The H₂O was filtered through a 0.2μfilter (Millipore, Billerica, Mass.). In addition, 75 mg of gentamicinwas added to the filtered H₂O and 600 mL of PEG 400 was added.

6.2 Preparation of Drug Formulations

Four different formulations were used for charging the donorcompartment. Drugs were made up in either 100% PG, 1:1:1 PG:ethanol:H₂O,2.36:1.18:1 PG:ethanol:H₂O, or a gel formulation. For the solutions, theappropriate amount of drug was weighed into a glass silanized culturetube and ethanol was added to get the drug into solution, then PG wasadded and water was added last. The gel formulation was comprised ofabsolute ethanol, H₂O, isopropyl myristate, Carbopol® 980, 0.1 N sodiumhydroxide solution and respective drug.

6.3 Permeation Experiments

(i) Dermatomed skin harvested from abdominoplasty and stored at −20° C.was used for the experiments. A PermeGear flow-through (In-Line,Hellertown, Pa.) diffusion cell system was used for the skin permeationstudies.

(ii) Diffusion cells were kept at 32° C. with a circulating water bath.Human epidermal skin was arranged in the diffusion cell with stratumcorneum (upper layer of skin) facing the donor compartment. Permeationarea of the skin was 0.95 cm². Data was collected from a human skindonor with three diffusion cells per treatment.

(iii) Receiver solution was 25% aqueous ethanol or 40% aqueous PEG 400and flow rate was adjusted to 0.8 mL/h. Each cell was charged with 50 or100 μL of the respective drug formulation (donor solution) or with 35 μLof gel formulation which was rubbed into the skin for 15 sec with aTeflon coated rod. The formulation was applied to ensure completecoverage. Diffusion cells were covered with a stopper for the durationof the study.

(iv) Samples were collected into scintillation vials in 3 h incrementsfor 24 h. All the samples were stored at 4° C. until extracted. A 1 mLaliquot of the 25% aqueous ethanol diffusion samples was placed intosilanized HPLC vials or an aliquot (500 μL) of the 40% PEG 400 diffusionsample was placed into a silanized HPLC vial and 500 μL of acetonitrilewas added to the sample, capped and vortexed.

(v) At the end of the experiment, the skin tissue was removed from thediffusion cell, rinsed with nanopure water, and blotted dry with a papertowel. The skin was tape stripped twice using book tape (Scotch™, 3M,St. Paul, Minn.) to remove drug formulation adhering to the tissuesurface. The area of skin in contact with the drug was excised, choppedup and placed in a pre-weighed scintillation vial. Ten mL ofacetonitrile was added to the vial and drug was extracted from the skinby shaking at room temperature overnight. The samples were analyzed byHPLC.

(vi) At the end of the experiment, a 10 μL aliquot of donor solution wasremoved and added to a scintillation vial containing 10 mL ofacetonitrile. The vials were vortexed and then sonicated for 15 min. Analiquot of 1 mL was removed and transferred into a silanized HPLC vialfor analysis.

7.0 Analytical Method

Column Brownlee ® C₈ reversed phase Spheri 5 μm, (4.6 × 220 mm) columnwith a Brownlee ® C₈ reversed phase 7 μm (3.2 × 150 mm) guard column orSymmetry ®C₁₈ 5 μm (2.1 × 150 mm) column Mobile 70:30 acetonitrile:0.05%trifluroacetic phase acid with 5% acetonitrile, 82:18 acetonitrile:0.05%trifluroacetic acid with 5% acetonitrile or 95:5 (74:21:5methanol:H₂O:THF):(95:5 H₂O:acetonitrile) Flow rate 0.5 mL/min or 1.5mL/min Wavelength 210 nm Injection 50 μL or 100 μL (diffusion samplesand volume respective standards) 10 μL or 20 μL (skin samples, donorsamples, and respective standards) Run time 7-21 min RetentionΔ⁹-tetrahydrocannabinol = 6.2-6.4, 11.4-12.4 min times ALL00117 =8.4-8.9 min ALL00118 = 12.7-13.2 min ALL00119 = 8.3-8.4, 14 min ALL00120= 5.1 min ALL00121 = 9.7-10.2 min ALL00122 = 9.5 min ALL00123 = 10.7 minALL00124 = 9.7-9.8, 19.8 min ALL00125 = 15.0 min

8.0 Data Analysis

The cumulative quantity of drug collected in the receiver compartmentwas plotted as a function of time. The flux value for a given experimentwas obtained from the slope of a steady state portion of the cumulativeamount of drug permeated versus time plot. Lag time was obtained fromthe x-intercept of the steady state portion of the cumulative amount ofdrug permeated vs. time plot. The combined results of the deliveredprodrug and Δ⁹-tetrahydrocannabinol from the prodrug are listed as“total Δ⁹-tetrahydrocannabinol.” These values represent the data astotal Δ⁹-tetrahydrocannabinol equivalents delivered in the form ofΔ⁹-tetrahydrocannabinol and/or prodrug.

Section III. Tables

TABLE 1 Δ⁹-Tetrahydrocannabinol and Δ⁹-tetrahydrocannabinol prodrugsMolecular Molecular Compound formula weight Δ⁹-tetrahydrocannabinolC₂₁H₃₀O₂ 314.46 ALL00117 C₃₀H₄₆O₇ 518.68 ALL00118 C₂₅H₃₇NO₃ 399.57ALL00119 C₃₁H₄₈O₈ 548.71 ALL00120 C₂₄H₃₃NO₄ 399.50 ALL00121 C₂₅H₃₅NO₄413.55 ALL00122 C₃₂H₄₈O₉ 576.72 ALL00123 C₂₅H₃₄O₅ 414.53 ALL00124C₂₆H₄₀N₂O₃ 428.61 ALL00125 C₂₆H₃₇NO₃ 411.58

TABLE 2 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2) and ALL00117(n = 3) with 100% PG donor solution 24 h 24 h Flux Lag skin conccumulative (nmol/ time Compound (μmol/g) amt (nmol) cm²/h) (h) Δ⁹- 74.8± 15.5 6.9 ± 2.1 — — tetrahydro- annabinol ALL00117 8.9 ± 7.1 (PD) — — —1.1 ± 0.0 (THC)

TABLE 3 Permeation data of Δ⁹-tetrahydrocannabinol (n = 3) and ALL00118(n = 3) with 1:1:1 PG:ethanol:H₂O donor solution 24 h 24 h Flux Lag skinconc cumulative (nmol/ time Compound (μmol/g) amt (nmol) cm²/h) (h) Δ⁹-59.4 ± 30.5 9.0 ± 5.9 0.93 ± 0.58 13.0 ± 1.8 tetrahydro- cannabinolALL00118 37.3 ± 23.2 (PD) — — — 7.1 ± 2.4 (THC)

TABLE 4 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2), ALL00117 (n= 1), and ALL00118 (n = 3) with gel formulation 24 h 24 h Flux Lag skinconc cumulative (nmol/ time Compound (μmol/g) amt (nmol) cm²/h) (h) Δ⁹-100.4 ± 5.8 1.5 ± 0.3 0.14 ± 0.03 11.2 ± 2.7 tetrahydro- cannabinolALL00117 13.8 ± 4.1 (PD) 1.7 ± 0.0 0.07 ± 0.00 — 0.7 ± 0.1 (THC)ALL00118 48.8 ± 30.2 (PD) — — — 65.9 ± 24.7 (THC)

TABLE 5 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2) with 1:1:1PG:ethanol:H₂O donor solution and higher flow rate 24 h 24 h Flux Lagskin conc cumulative (nmol/ time Compound (μmol/g) amt (nmol) cm²/h) (h)Δ⁹- 133.8 ± 52.3 6.0 ± 2.1 0.67 ± 0.15 8.9 ± 7.2 tetrahydro- cannabinol

TABLE 6 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2) with 1:1:1PG:ethanol:H₂O donor solution and comparison of two different receiverfluids 24 h 24 h Flux Lag skin conc cumulative (nmol/ time Compound(μmol/g) amt (nmol) cm²/h) (h) Δ⁹- 24.1 ± 5.2  9.4 ± 0.2 0.70 ± 0.01 6.9± 0.2 tetrahydro- cannabinol (25% aqueous ethanol) Δ⁹- 17.4 ± 11.6 28.6± 3.2 1.79 ± 0.39 6.4 ± 1.6 tetrahydro- cannabinol (40% aqueous PEG 400)

TABLE 7 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2), ALL00120 (n= 3), ALL00121 (n = 2) and ALL00123 (n = 3) with 2.36:1.18:1PG:ethanol:H₂O donor solution 24 h 24 h Flux Lag skin conc cumulative(nmol/ Flux time Compound (μmol/g) amt (nmol) cm²/h) enhancement (h)Δ⁹-tetrahydrocannabinol (THC) 75.2 ± 33.1 43.1 ± 4.8 3.1 ± 0.2 — 9.0 ±2.9 total Δ⁹-tetrahydrocannabinol * 50.2 ± 7.1  39.3 ± 6.6 2.7 ± 0.50.87 8.4 ± 1.3 ALL00120 47.1 ± 6.3  30.5 ± 7.0 2.0 ± 0.5 8.1 ± 1.6 THCfrom ALL00120 3.1 ± 1.1  8.8 ± 1.2 0.6 ± 0.1 9.2 ± 0.8 totalΔ⁹-tetrahydrocannabinol * 72.3 ± 54.0 22.4 ± 6.5 1.5 ± 0.4 0.66 8.5 ±0.8 ALL00121 72.3 ± 54.0 18.5 ± 5.6 1.2 ± 0.3 8.3 ± 0.5 THC fromALL00121 ND  3.9 ± 1.0 0.3 ± 0.0 8.8 ± 1.2 totalΔ⁹-tetrahydrocannabinol * 60.7 ± 15.9 48.7 ± 7.4 3.1 ± 0.6 1.03 7.6 ±1.5 ALL00123 ND ND — — THC from ALL00123 60.7 ± 15.9 48.7 ± 7.4 3.1 ±0.6 7.6 ± 1.5 * total THC = total Δ⁹-tetrahydrocannabinol equivalentsdelivered in the form of Δ⁹-tetrahydrocannabinol and/or prodrug

TABLE 8 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2), ALL00120 (n= 3), ALL00121 (n = 2) and ALL00123 (n = 3) with gel formulation 24 h 24h Flux Lag skin conc cumulative (nmol/ Flux time Compound (μmol/g) amt(nmol) cm²/h) enhancement (h) Δ⁹-tetrahydrocannabinol (THC)  40.9 ± 14.710.7 ± 2.1 0.62 ± 0.23 — 5.3 ± 3.3 total Δ⁹-tetrahydrocannabinol * 47.9± 2.8 — — — — ALL00120 44.8 ± 1.6 — — — THC from ALL00120  3.1 ± 2.1 — —— total Δ⁹-tetrahydrocannabinol * 33.2 ± 7.2 10.5 ± 0.5 0.53 ± 0.05 0.853.0 ± 2.8 ALL00121 33.2 ± 7.2  8.8 ± 0.1 0.38 ± 0.03 1.4 ± 0.0 THC fromALL00121 ND  1.7 ± 0.4 0.15 ± 0.01 11.6 ± 4.1  totalΔ⁹-tetrahydrocannabinol * 110.4 ± 22.2 17.5 ± 4.0 0.67 ± 0.18 1.08 —ALL00123 110.4 ± 22.2  2.3 ± 1.5 0.15 ± 0.07 — THC from ALL00123 ND 15.2± 2.5 0.52 ± 0.13 5.6 ± 4.3 * total THC = total Δ⁹-tetrahydrocannabinolequivalents delivered in the form of Δ⁹-tetrahydrocannabinol and/orprodrug

TABLE 9 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2), ALL00119 (n= 3), ALL00122 (n = 2) and ALL00124 (n = 2) with 2.36:1.18:1 pH = 5.5PG:ethanol:H₂O donor solution 24 h 24 h Flux Lag skin conc cumulative(nmol/ Flux time Compound (μmol/g) amt (nmol) cm²/h) enhancement (h)Δ⁹-tetrahydrocannabinol (THC) 16.1 ± 0.5 16.3 ± 7.3  1.3 ± 0.5 — 11.4 ±0.6  total Δ⁹-tetrahydrocannabinol * 13.6 ± 7.5 ND — — — ALL00119 13.6 ±7.5 ND — — THC from ALL00119 ND ND — — total Δ⁹-tetrahydrocannabinol *56.5 ± 3.8 6.0 ± 0.7  0.5 ± 0.03 0.36 11.0 ± 0.8  ALL00122 52.7 ± 3.2 ND— — THC from ALL00122  3.8 ± 0.6 6.0 ± 0.7 0.3 ± 0.0 11.0 ± 0.8  totalΔ⁹-tetrahydrocannabinol *  67.4 ± 11.3 145.2 ± 105.2 9.9 ± 6.2 7.35 9.1± 1.8 ALL00124 17.3 ± 0.4 138.7 ± 101.2 9.4 ± 5.9 9.1 ± 2.0 THC fromALL00124  50.1 ± 11.0 6.5 ± 4.0 0.5 ± 0.4 7.6 ± 3.3 * total THC = totalΔ⁹-tetrahydrocannabinol equivalents delivered in the form ofΔ⁹-tetrahydrocannabinol and/or prodrug

TABLE 10 Permeation data of Δ⁹-tetrahydrocannabinol (n = 3), ALL00124 (n= 2), and ALL00125 (n = 3) with 2.36:1.18:1 pH = 5.5 PG:ethanol:H₂Odonor solution 24 h 24 h Flux Lag skin conc cumulative (nmol/ Flux timeCompound (μmol/g) amt (nmol) cm²/h) enhancement (h)Δ⁹-tetrahydrocannabinol (THC) 7.4 ± 0.6  33.6 ± 11.2 2.7 ± 1.1 — 10.8 ±1.4 total Δ⁹-tetrahydrocannabinol * 4.8 ± 0.4 253.3 ± 56.9 16.7 ± 0.4 6.13  1.3 ± 0.0 ALL00124 4.3 ± 0.3 245.2 ± 54.1 16.1 ± 0.1   1.4 ± 0.0THC from ALL00124 0.5 ± 0.1  9.3 ± 2.9 0.6 ± 0.2  1.1 ± 0.0 totalΔ⁹-tetrahydrocannabinol * 1.4 ± 1.0 17.4 ± 8.8 1.3 ± 0.6 0.49 10.7 ± 1.7ALL00125 ND ND — — THC from ALL00125 1.4 ± 1.0 17.4 ± 8.8 1.3 ± 0.6 10.7± 1.7 * total THC = total Δ⁹-tetrahydrocannabinol equivalents deliveredin the form of Δ⁹-tetrahydrocannabinol and/or prodrug

TABLE 11 Plasma stability of Δ⁹-tetrahydrocannabinol prodrugs % Prodrugat time (h) Prodrug 0.1 1 2 3 5 22 24 42 ALL00118 100 94 — — — 86 81 15 ALL00119 100 82 — — — 64 51 0 ALL00120 70 8 — — — 0 0 0 ALL00121 100 50— — — 10 14 0 ALL00122 0 0 — — — 0 0 0 ALL00123 0 0 — — — 0 0 0 ALL0012497 97 97 96 94 — 71 — ALL00125 100 — 77 — 55 0 0 0

Example 2

Section I. Summary

The objective was to synthesize additional Δ⁹-tetrahydrocannabinolprodrugs and assess the permeation of Δ⁹-tetrahydrocannabinol and itsprodrugs through human abdominal skin in vitro. Four additionalΔ⁹-tetrahydrocannabinol prodrugs were synthesized, three of which weretested. Synthesized prodrugs of Δ⁹-tetrahydrocannabinol were analyzedfor plasma stability to monitor the rate of conversion toΔ⁹-tetrahydrocannabinol. Potential candidates would convert readily toΔ⁹-tetrahydrocannabinol in plasma whereas there would only be minimalconversion of stable prodrugs. Flow through diffusion cells were usedfor the permeation studies. The receiver used for the permeation studieswas 40% aqueous PEG (polyethylene glycol) 400. Donor solution wascomprised of a rubbed in gel formulation. The flux and lag time valuesof Δ⁹-tetrahydrocannabinol and Δ⁹-tetrahydrocannabinol prodrugs wereobtained from the permeation profiles. Drug accumulation in the skinafter a 24 h diffusion experiment was determined as μmol/g wet tissueweight.

Section II. Methodology

1.0 Purpose: Synthesize Δ⁹-tetrahydrocannabinol prodrugs and assess thehuman skin permeation of Δ⁹-tetrahydrocannabinol andΔ⁹-tetrahydrocannabinol prodrugs in vitro. The following compounds weresynthesized:

2.0 Skin Details

The skin samples used in the following experiments were obtained fromabdominal reduction surgery and dermatomed to a thickness ofapproximately 200 μm. The skin samples used herein were frozen at −20°C. for less than six months.

3.0 Chemicals

Trifluoroacetic acid, triethylamine, gentamicin sulfate, acetone,(t-butyldimethylsilyloxy)acetic acid, dichloromethane (DCM),4-dimethylaminopyridine (DMAP), and sodium bicarbonate were purchasedthrough Fisher Scientific (Fairlawn, N.J.). Methanol (HPLC grade),acetonitrile (HPLC grade), ethyl acetate, hexane,N,N′-dicyclohexylcarbodiimide, 3-dimethylaminopropionic acidhydrochloride and polyethylene glycol 400 (PEG 400) were purchasedthrough VWR (West Chester, Pa.). Absolute ethanol USP, triethylaminetrihydrofluoride, ribonic acid diacetonide, and Δ⁹-tetrahydrocannabinolwere purchased from Sigma-Aldrich (St. Louis, Mo.). Anhydrous sodiumsulfate was purchased from UK Stores (Lexington, Ky.). Argon andpre-purified nitrogen were purchased from Scott Gross Company(Lexington, Ky.). Carbopol® 980 was obtained from Noveon, Inc.(Cleveland, Ohio). Nanopure water was obtained from a BarnsteadNANOpure® DIamond™ Ultrapure water filtration system (Dubuque, Iowa).

4.0 Synthesis of Δ⁹-tetrahydrocannabinol prodrugs

4.1 Synthesis of ALL00153 (Δ⁹-Tetrahydrocannabinol3-(dimethylamino)propionate).

THC (46 mg, 0.00015 mol), 3-dimethylaminopropionic acid hydrochloride(28 mg, 0.00018 mol), and DMAP (27 mg, 0.00022 mol) were combined in 1mL dry dichloromethane. The solution was stirred for 5 min at ambienttemperature. DCC (45 mg, 0.00022 mol) was added to the mixture. Themixture was allowed to stir for 3 h at ambient temperature.Dichloromethane was removed from the reaction mixture under a stream ofnitrogen. The sample was reconstituted in acetonitrile and the solidsremoved by filtration. The solution was reduced to a small volume undernitrogen. ALL00153 was isolated using a semi-preparatory C8 HPLC columnwith ACN:pH 3 buffer (80:20) as mobile phase. The ACN was removed fromthe eluent fraction containing ALL00153 by rotary evaporation underreduced pressure. The pH of the remaining aqueous layer was adjusted topH 8 using 1% sodium bicarbonate. The aqueous layer was partitioned withthree times with DCM and the combined DCM fractions dried over sodiumsulfate. DCM was removed by rotary evaporation. The purified productappeared as transparent, viscous oil with light amber color.

ALL00153 was analyzed by LC/MS in electrospray positive ion mode. Themass of the compound was confirmed by the observation of the molecularion at 414.342 (M+1, 100%).

For ALL00153, the 1H NMR (400 MHz, CDCl₃) was as follows: δ□=6.55(1H, d,J=1.8, H−4); 6.41(1H, d, J=1.8, H−2); 5.93-5.97(1H, m, H−10);3.02-3.09(1H, m, H−10a); 2.70-2.84(4H, m, COCH₂CH₂); 2.45-2.53(2H, m,benzylic CH₂); 2.32(6H, s, N(CH₃)₂); 2.10-2.17(2H, m); 1.86-1.95(1H, m);1.64-1.73(4H, m); 1.52-1.64(2H, m); 1.41(3H, s, 6β-Me); 1.23-1.40(5H,m); 1.08(3H, s, 6α-Me); 0.88(3H, t, J=7.0, CH₂ CH₃ ).

4.2 Synthesis of ALL00154 (Δ⁹-Tetrahydrocannabinol glycolate).

To a stirred solution of THC (78.6 mg, 0.25 mmol) and(t-butyldimethylsilyloxy)acetic acid (71.4 mg, 0.375 mmol) indichloromethane (0.5 mL), 4-dimethylaminopyridine was added (6.1 mg,0.05 mmol) followed by N,N′-dicyclohexylcarbodiimide (103.2 mg, 0.5mmol). The mixture was stirred at ambient temperature for 2 h.Additional amounts of (t-butyldimethylsilyloxy)acetic acid (80 mg, 0.42mmol) and N,N′-dicyclohexylcarbodiimide (110 mg, 0.53 mmol) were addedand stirring was continued for 1 h. The mixture was diluted with hexane(1.5 mL), filtered, concentrated under a reduced pressure andchromatographed on silica gel with hexane-ethyl acetate (gradient 50:1,40:1) to afford Δ⁹-tetrahydrocannabinol (t-butyldimethylsilyloxy)acetate(69.9 mg, 57.4%) as an oil.

Next, Δ⁹-tetrahydrocannabinol (t-butyldimethylsilyloxy)acetate (67.8 mg)was dissolved in dichloromethane (0.25 mL), cooled to −15° C. andtreated with 0.25 mL of cold 2N solution of triethylaminetrihydrofluoride in dichloromethane. The reaction mixture was left at 5°C. for 48 h. The mixture was poured to an excess of aqueous saturatedsodium bicarbonate/ethyl acetate cooled to 0° C. with vigorous stirring.The aqueous layer was extracted twice with ethyl acetate. The combinedorganic extracts were dried over anhydrous sodium sulfate andconcentrated. The residue was chromatographed on silica gel withhexane-ethyl acetate (gradient 30:1, 20:1, 10:1) to afford 38.5 mg (74%)of A 9-tetrahydrocannabinol glycolate (ALL00154) as an oil.

For ALL00154, the 1H NMR (400 MHz, CDCl₃) was as follows: δ□=6.58(1H, d,J=1.6, H−4); 6.43(1H, d, J=2.0, H−2); 5.82-5.87(1H, m, H−10);4.36-4.50(2H, AB part of ABX, 8 lines, COCH₂); 3.01-3.09(1H, m, H−10a);2.46-2.54(2H, m, benzylic CH₂); 2.40(1H, t(X part of ABX), J=5.6, OH);2.10-2.20(2H, m); 1.86-1.95(1H, m); 1.62-1.72(4H, m); 1.52-1.62(2H, m);1.41(3H, s, 6β-Me); 1.23-1.40(5H, m); 1.09(3H, s, 6α-Me); 0.88(3H, t,J=7.0, CH₂ CH₃ ).

4.3 Synthesis of ALL00155 (Δ⁹-Tetrahydrocannabinol D-ribonate).

THC (63.8 mg, 0.00018 m) and ribonic acid diacetonide((2R,3R,4R)-2,3:4,5-di-O-isopropylidene-2,3,4,5-tetrahydroxypentanoicacid) (63.8 mg, 0.00026 m) were combined in 0.5 mL DCM. DMAP (2.1 mg,0.00002 m) was added and the solution stirred briefly. DCC (535.5 mg,0.00026 m) was added and the mixture stirred for 2 h. Hexane (1.5 mL)was added and the mixture filtered. The filtrate was reduced to a smallvolume under nitrogen. The product (62.5 mg) was isolated using silicacolumn chromatography and a 80:20 hexane:ethyl acetate.

For Δ⁹-tetrahydrocannabinol D-ribonate diacetonide, the 1H NMR (400 MHz,CDCl₃) was as follows: δ□=6.56(1H, d, J_(AB)=2.0, H−4); 6.54(1H, d,J_(AB)=1.6, H−2); 5.99-6.03(1H, m, H−10); 4.94(1H, d, J=6.4); 4.39(1H,dd, J₁=9.2, J₂=6.4); 4.21-4.27(1H, m); 4.14(1H, dd, J₁=8.8, J₂=6.4);4.01(1H, dd, J₁=8.8, J₂=5.2); 3.10-3.18(1H, m, H−10a); 2.44-2.52(2H, m,benzylic CH₂); 2.08-2.17(2H, m); 1.84-1.92(1H, m); 1.62-1.70(4H, m);1.51-1.60(2H, m); 1.50(3H, s, acetonide CH₃); 1.42(3H, s, acetonideCH₃); 1.41(3H, s, 6β-Me); 1.38(3H, s, acetonide CH₃); 1.23-1.38(5H, m);1.09(3H, s, 6α-Me); 0.87(3H, t, J=7.0, CH₂ CH₃ ).

It is understood that a person of ordinary skill in the art would beable to deprotect Δ⁹-tetrahydrocannabinol D-ribonate diacetonide to formALL00155, using one of many available acetonide deprotection methods.

4.4 Synthesis of ALL00156 (Δ⁹-Tetrahydrocannabinol phosphate ammoniumsalt).

To a stirred solution of solution of THC (10.9 mg, 0.0347 mmol) inanhydrous THF (0.2 mL) at 0° C. under an argon atmosphere was addedtriethylamine (0.0314 mL, 0.2253 mmol) followed by phosphorusoxychloride (0.00635 mL, 0.0693 mmol). After stirring for 2 hr at 0° C.,triethylamine (0.020 mL) was added followed by water (0.030 mL). Themixture was stirred at ambient temperature for 24 h and the product waspurified using a Waters SymmetryPrep® C8 column (7.8×300 mm, 7 μmparticle size) and mobile phase consisting of 70:30 (0.5% Ammoniumcarbonate:ACN) and UV detection at 230 nm (RT 15 min).

For ALL00156, the ¹H NMR (400 MHz, CDCl₃-CD₃OD ˜10:1) was as follows:δ=6.80(1H, br s, H−4); 6.41 (1H, br s, H−10); 6.38(1H, br s, H−2);4.02(8H, br s, NH₄); 3.30-3.35(1H, m); 2.45(2H, t, J=7.8, ArCH₂);2.09-2.18(2H, m); 1.86-1.94(1H, m); 1.50-1.71(6H, m); 1.40(3H, s,6β-Me); 1.23-1.40(5H, m); 1.07(3H, s, 6α-Me); 0.87 (3H, t, J=6.8, CH₂ CH₃).

ALL00156 was analyzed by LC/MS in electrospray negative ion mode. Themass of the compound was confirmed by the observation of theTHC-P(O)(OH)O⁻ ion at 393.090 (M−1, 100%) and the dimmer at 787.709(13.5%).

5.0 Plasma Stability Studies

An approximated 1 mg/mL stock solution of each prodrug was prepared in100 μL of ethanol and 900 μL of acetonitrile. Next, 10 μL of stock wasspiked into 1 mL of plasma and vortexed. The samples were kept sealed inan amber vial and samples were obtained to analyze for bioconversion toparent drug.

6.0 In Vitro Skin Permeation Studies

6.1 Preparation of Receiver Fluid

The receiver fluid was prepared by measuring 600 mL of nanopure H₂O intoa graduated cylinder. The H₂O was filtered through a 0.2μ filter(Millipore, Billerica, Mass.). Next, 50 mg of gentamicin was added tothe filtered H₂O and 400 mL of PEG 400 was added.

6.2 Preparation of Drug Formulations

Drugs were made up in a gel formulation. The gel formulation wascomprised of absolute ethanol, H₂O, Carbopol® 980, 0.1 N sodiumhydroxide solution and respective drug.

6.3 Permeation Experiments

Dermatomed skin harvested from abdominoplasty and stored at −20° C. wasused for the experiments. A PermeGear flow-through (In-Line, Hellertown,Pa.) diffusion cell system was used for the skin permeation studies.

Diffusion cells were kept at 32° C. with a circulating water bath. Humanepidermal skin was arranged in the diffusion cell with stratum corneum(upper layer of skin) facing the donor compartment. Permeation area ofthe skin was 0.95 cm². Data was collected from a human skin donor withthree diffusion cells per treatment.

Receiver solution was 40% aqueous PEG 400 and flow rate was adjusted to0.8 mL/h. Each cell was charged with 50 μL of gel formulation which wasrubbed into the skin for 15 sec with a Teflon coated rod. Theformulation was applied to ensure complete coverage. Diffusion cellswere covered with a cap for the duration of the study.

Samples were collected into scintillation vials in 3 h increments for 24h. All the samples were stored at 4° C. until extracted. An aliquot (500μL) of the 40% PEG 400 diffusion sample was placed into a silanized HPLCvial and 500 μL of acetonitrile was added to the sample, capped andvortexed.

At the end of the experiment, the skin was washed with 700 μL ofacetonitrile and from the 700 μL of acetonitrile an aliquot of 10 μL wasdiluted in a scintillation vial containing 10 mL of acetonitrile. Thevials were vortexed and then sonicated for 15 min. An aliquot of 1 mLwas removed and transferred into a silanized HPLC vial for analysis.

At the end of the experiment, the skin tissue was removed from thediffusion cell, rinsed with nanopure water for 30 sec, and wiped offtwice with an alcohol pad. The skin was tape stripped twice using booktape (Scotch™, 3M, St. Paul, Minn.) to remove drug formulation adheringto the tissue surface. The area of skin in contact with the drug wasexcised, chopped up and placed in a pre-weighed scintillation vial. TenmL of acetonitrile was added to the vial and drug was extracted from theskin by shaking at room temperature overnight. The samples were analyzedby HPLC.

7.0 Analytical Method

Column Brownlee ® C8 reversed phase Spheri 5 μm, (4.6 × 220 mm) columnwith a Brownlee ® C8 reversed phase 7 μm (3.2 × 150 mm) guard columnMobile 90:10 acetonitrile:0.05% trifluroacetic phase acid with 5%acetonitrile or 65:35 acetonitrile:0.05% trifluroacetic acid with 5%acetonitrile Flow rate 1.5 mL/min Wavelength 210 nm Injection 100 μL(diffusion samples and volume respective standards) 20 μL (skin samples,donor samples, and respective standards) Run time 20-23 min RetentionΔ9-tetrahydrocannabinol = 3.9, 21.2 min times ALL00153 = 17.9 minALL00154 = 20.0 min

8.0 Data Analysis

The cumulative quantity of drug collected in the receiver compartmentwas plotted as a function of time. The flux value for a given experimentwas obtained from the slope of a steady state portion of the cumulativeamount of drug permeated versus time plot. Lag time was obtained fromthe x-intercept of the steady state portion of the cumulative amount ofdrug permeated versus time plot. The combined results of the deliveredprodrug and Δ⁹-tetrahydrocannabinol from the prodrug are listed as“total Δ⁹-tetrahydrocannabinol.” These values represent the data astotal Δ⁹-tetrahydrocannabinol equivalents delivered in the form ofΔ⁹-tetrahydrocannabinol and/or prodrug.

Section III. Tables

TABLE 12 Δ⁹-Tetrahydrocannabinol and Δ⁹-tetrahydrocannabinol prodrugsMolecular Molecular Compound formula weight Δ⁹-tetrahydrocannabinolC₂₁H₃₀O₂ 314.46 ALL00153 C₂₆H₃₉NO₃ 413.59 ALL00154 C₂₃H₃₂O₄ 372.50ALL00155 C₂₆H₃₈O₇ 462.58

TABLE 13 Permeation data of THC (n = 3), ALL00153 (n = 3), and ALL00154(n = 1) in gel formulation with 40% aqueous PEG 400 receiver fluid 24 h24 h Flux Lag skin conc cumulative (nmol/ Flux time Compound (μmol/g)amt (nmol) cm²/h) enhancement (h) tetrahydrocannabinol (THC) 3.6 ± 1.73.1 ± 0.8 0.17 ± 0.02  — 4.6 ± 3.2 total tetrahydrocannabinol* 2.9 ± 0.23.1 ± 1.3 0.18 ± 0.002 1.06 8.7 ± 6.7 ALL00153  1.6 ± 0.03 ND — — THCfrom ALL00153 1.3 ± 0.1 3.1 ± 1.3 0.18 ± 0.002 8.7 ± 6.7 totaltetrahydrocannabinol* 2.6 ± 1.5 40.7± 3.37± 19.82 12.4± ALL00154 2.6 ±1.5 39.2± 3.23± 12.2± THC from ALL00154 ND  1.6± — — *total THC = totaltetrahydrocannabinol equivalents delivered in the form oftetrahydrocannabinol and/or prodrug

TABLE 14 Plasma stability of Δ9-tetrahydrocannabinol prodrugs % Prodrugat time (h) Prodrug 0 1 21 24 ALL00153 98 72 48 41 ALL00154 95 0 0 0

Example 3

Section I. Summary

The objective was to synthesize additional Δ⁹-tetrahydrocannabinolprodrugs and assess the permeation of Δ⁹-tetrahydrocannabinol and itsprodrugs through human abdominal skin in vitro. TenΔ⁹-tetrahydrocannabinol prodrugs were synthesized and eight were tested.Synthesized prodrugs of Δ⁹-tetrahydrocannabinol were analyzed for plasmastability to monitor the rate of conversion to Δ⁹-tetrahydrocannabinol.Potential candidates would convert readily to Δ⁹-tetrahydrocannabinol inplasma whereas stable prodrugs would convert very little. The procedurewas performed to screen out compounds with no bioconversion to theparent drug. Flow through diffusion cells were used for the permeationstudies. The receiver fluid used for the permeation studies was 40%aqueous PEG (polyethylene glycol) 400. Donor solution was comprised of90:8:2 propylene glycol (PG):H₂O:isopropyl myristate (IPM). The flux andlag time values of Δ⁹-tetrahydrocannabinol and Δ⁹-tetrahydrocannabinolprodrugs were obtained from the permeation profiles. Drug accumulationin the skin after a 24 h diffusion experiment was determined as μmol/gwet tissue weight.

Section II. Methodology

1.0 Purpose: Synthesize Δ⁹-tetrahydrocannabinol prodrugs and assess thehuman skin permeation of Δ⁹-tetrahydrocannabinol andΔ⁹-tetrahydrocannabinol prodrugs in vitro. The following compounds weresynthesized:

2.0 Skin Details

The skin samples used in the following experiments were obtained fromabdominal reduction surgery and dermatomed to a thickness ofapproximately 200 μm. The skin samples used herein were frozen at −20°C. for less than six months.

3.0 Chemicals

Trifluoroacetic acid, triethylamine, gentamicin sulfate, isopropylmyristate (IPM), dichloromethane, sodium bicarbonate,4-dimethylaminopyridine, t-butyldimethylsilyl chloride, 1-octanethiol,R-(+)-1-benzylglycerol, and Fmoc-N-(4-hydroxybutyl)carbamate werepurchased through Fisher Scientific (Fairlawn, NJ). Methanol (HPLCgrade), acetonitrile (HPLC grade), N,N′-dicyclohexylcarbodiimide,1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), imidazole, zinctrifluoromethanesulfanate, N,N-dimethylglycine , and polyethylene glycol400 (PEG 400) were purchased through VWR (West Chester, Pa.).Delta-9-Tetrahydrocannabinol, propylene glycol (PG), triethylene glycol,methyl (S)-(−)-2,2-dimethyl-1,3-dioxolane-4-carboxylate, methyl(R)-(+)-2,2-dimethyl-1,3-dioxolane-4-carboxylate, (R)-(−)-Solketal,N-(2-nitrophenylsulfenyl)glycine dicyclohexylammonium salt, triphosgene,triethylamine trihydrofluroride, and thiophenol were purchased fromSigma-Aldrich (St. Louis, Mo.). Chloroform and anhydrous sodium sulfatewere obtained from the University of Kentucky Chemical Stores(Lexington, Ky.). Argon and pre-purified nitrogen were purchased fromScott Gross Company (Lexington, Ky.). Nanopure water was obtained from aBarnstead NANOpure® DIamond™ Ultrapure water filtration system (Dubuque,Iowa). The following compounds were synthesized according to literatureprocedures: 5-carboxy-2,2,5-trimethyl-1,3-dioxane (Macromolecules, 31,4061, 1998), 3,6,9,12-tetraoxatridecanoic acid (Macromolecules, 39 (12),3978 -3979, 2006.), and N-(2-nitrophenylsulfenyl)-β-alanine (JACS, 85,3660, 1963).

4.0 Synthesis of Δ⁹-Tetrahydrocannabinol (Δ⁹-THC) Prodrugs

4.1 Synthesis of ALL00117 (Δ⁹-Tetrahydrocannabinol3,6,9,12-tetraoxatridecanoyl ester)

THC (200 mg, 0.0004 mol) was dissolved in about 10 mL ofdichloromethane. The mixture was stirred at ambient temperature for 5min. Next, 3,6,9,12-tetraoxatridecanoic acid (43.3 mg, 0.195 mmol) indichloromethane (1.75 mL) was added followed by 4-dimethylaminopyridine(1.8 mg, 0.015 mmol) and N,N′-dicyclohexylcarbodiimide (49.5 mg, 0.24mmol). The mixture was stirred at ambient temperature overnight. Themixture was filtered, concentrated under a reduced pressure andchromatographed on silica gel with hexane-ethyl acetate (gradient 4:1,2:1, 1:1, 0:1). Fractions containing the product were concentrated undera reduced pressure, dissolved in hexane with a few drops of ethylacetate, filtered and concentrated again to afford ALL00117 (65.5 mg,65%) as an oil.

For ALL00117, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ=6.57(1H, d,J=1.8, H−4); 6.42(1H, d, J=1.8, H−2); 5.86-6.90 (1H, m, H−10); 4.42(2H,s, OCH₂CO₂); 3.88-3.76(2H, m, PEG); 3.75-3.64(8H, m, PEG); 3.58-3.54(2H,m, PEG); 3.39(s, 3H, CH₂OCH₃); 3.11-3.03(1H, m, H−10a); 2.49(2H, t,J=8.3, ArCH₂); 2.09-2.17(2H, m); 1.85-1.94 (1H, m); 1.62-1.70(4H, m);1.52-1.62(2H, m); 1.41(3H, s, 6β-Me); 1.24-1.41(5H, m); 1.09(3H, s,6α-Me); 0.88 (3H, t, J=7.0, CH₂CH₃).

4.2 Synthesis of ALL00118 (Δ⁹-Tetrahydrocannabinol N,N-dimethylglycylester).

The same procedure as for ALL00117 (reaction time), starting fromN,N-dimethylglycine, THC (150 mg, 0.3 mmol),N,N′-dicyclohexylcarbodiimide (49.5 mg, 0.24 mmol),4-dimethylaminopyridine (1.8 mg, 0.015 mmol) in dichloromethane (1.75mL) afforded 8 mg (4%) of ALL00118 as an oil.

For ALL00118, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ=6.55(1H, d,J=1.8, H−4); 6.41(1H, d, J=1.8, H−2); 5.89-5.92 (1H, m, H−10); 3.43(2H,s, COCH₂); 3.04-3.12 (1H, m, H−10a); 2.49(2H, t, J=7.8, ArCH₂); 2.44(6H,s, _(N)(_(CH3))₂)_(;) 2.09-2.16(2H, m); 1.85-1.93 (1H, m); 1.62-1.70(4H,m); 1.52-1.61(2H, m); 1.40(3H, s, 6β-Me); 1.23-1.40(5H, m); 1.08(3H, s,6α-Me); 0.88 (3H, t, J=7.0, CH₂CH₃).

4.3 Synthesis of ALL00126 (Δ⁹-Tetrahydrocannabinol(R)-2,3-dihydroxypropyl carbonate)

The (S)-2,3 -Bis(t-butyldimethylsilyloxy)propan-1-ol was prepared from(R)-(+)-1-benzylglycerol via reaction with t-butyldimethylsilyl chloridein the presence of imidazole and subsequent catalytic debenzylation (10%Pd/C, ethyl acetate).

To a stirred solution of (S)-2,3-bis(t-butyldimethylsilyloxy)propan-1-ol(129 mg, 0.3836 mmol) in dichloromethane (0.6 mL) at 0° C. under anargon atmosphere triethylamine (38.8 mg, 53.5 μL, 0.3836 mmol) wasadded, followed by triphosgene (37.9 mg, 0.1279 mmol) and stirring wascontinued at 0° C. for 3 h. The mixture was subsequently transferred toa solution of THC (88.0 mg, 0.28 mmol) and triethylamine (38.8 mg, 53.5μL, 0.3836 mmol) in dichloromethane (0.6 mL) at 0° C. under an argonatmosphere with stirring. Stirring continued at ambient temperature for3 h. The mixture was diluted with ethyl acetate (3 mL) and filtered. Thefiltrate was concentrated, dissolved in ethyl acetate (1 mL) andconcentrated again. The residue was chromatographed on silica gel withhexane-ethyl acetate (gradient 40:1, 30:1, 20:1) to afford 120.1 mg(65%) of THC (S)-2,3-bis(t-butyldimethylsilyloxy)propyl carbonate as anoil.

THC (S)-2,3-bis(t-butyldimethylsilyloxy)propyl carbonate was dissolvedin dichloromethane (200 μL), cooled to −15° C. and treated with 200 μLof cold 2N solution of triethylamine trihydrofluoride. The reactionmixture was left at 5° C. for 65 h. The mixture was poured to an excessof aqueous saturated sodium bicarbonate/ethyl acetate cooled to 0° C.with vigorous stirring. The aqueous layer was extracted twice with ethylacetate. The combined organic extracts were dried over anhydrous sodiumsulfate and concentrated. The residue was chromatographed on silica gelwith hexane-ethyl acetate (gradient 3:1, 2:1, 1:1) to afford 60.5 mg(77%) of THC (R)-2,3-dihydroxypropyl carbonate (ALL00126) as an oil.

For ALL00126, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.58 (1H,d, J=1.8, H−4); 6.50 (1H, d, J=1.6, H−2); 5.96-6.00 (1H, m, H−10);4.30-4.39 (2H, m); 4.00-4.08 (1H, m); 3.64-3.81 (2H, m); 3.11-3.19 (1H,m, H−10a); 2.58 (1H, d, J=5.1); 2.46-2.53 (2H, m); 2.11-2.20 (2H, m);2.07 (1H, t br, J=6.0); 1.86-1.95 (1H, m); 1.62-1.72 (4H, m); 1.52-1.62(2H, m); 1.41 (3H, s, 6β-Me); 1.23-1.40 (5H, m); 1.09 (3H, s, 6α-Me);0.88 (3H, t, J=7.0, CH₂CH₃).

4.4 Synthesis of ALL00127 (Δ⁹-Tetrahydrocannabinol 4-aminobutylcarbonate)

To a stirred solution of Fmoc-N-(4-hydroxybutyl)carbamate (40.2 mg,0.129 mmol) in dry dichloromethane (0.5 mL) at 0° C. under an argonatmosphere triethylamine (13.05 mg, 18 μL, 0.129 mmol) was added,followed by triphosgene (13.4 mg, 0.04515 mmol) and stirring wascontinued at 0° C. for 2 h. Mixture was subsequently transferred to asolution of THC (47.2 mg, 0.15 mmol) and triethylamine (15.2 mg, 20.9μL, 0.15 mmol) in dichloromethane (0.5 mL) at 0° C. under an argonatmosphere while stirring. Stirring was continued at ambient temperaturefor 2 h. Mixture was diluted with ethyl acetate (3 mL) and filtered. Thefiltrate was concentrated, dissolved in ethyl acetate (1 mL) andconcentrated again to afford 87.3 mg of a crude product. The crudeproduct was purified by preparative normal phase HPLC (ZORBAX RX-SIL,9.4×250 mm, 5μm) with hexane-ethyl acetate (3:1) to afford 41.8 mg (50%)of THC 4-(Fmoc-amino)butyl carbonate as an oil.

THC 4-(Fmoc-amino)butyl carbonate (65.7 mg, 0.10 mmol) was dissolved in1.5 mL of 10% (v/v) solution of 1-octanethiol in acetonitrile. Asolution of DBU (10% (v/v), 37.2 μL) was added and the mixture wasstirred at ambient temperature for 5 min. The second portion of DBUsolution (37.2 μL) was added and stirring was continued at ambienttemperature for 15 min. Mixture was loaded directly on silica gel andchromatographed with dichloromethane-methanol (gradient 1:0, 30:1, 20:1,10:1, 5:1). The combined fractions containing the product(Δ⁹-Tetrahydrocannabinol 4-aminobutyl carbonate) were diluted withchloroform, concentrated at 25° C. to ˜0.3 mL, diluted with chloroformand concentrated. The remaining oil (29 mg, 67%) was immediatelydissolved in chloroform and was stored at −20° C.

For ALL00127, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.56 (1H,d, J=1.8, H−4); 6.50 (1H, d, J=1.8, H−2); 5.98-6.12 (1H, m, H−10);4.20-4.32 (2H, m); 3.11-3.19 (1H, m, H−10a); 2.76 (2H, t, J=7.0); 2.49(2H, t, J=7.8); 2.10-2.18 (2H, m); 1.87-1.94 (1H, m); 1.75-1.83 (2H, m);1.63-1.72 (4H, m); 1.50-1.63 (6H, m); 1.41 (3H, s, 6β-Me); 1.23-1.40(5H, m); 1.09 (3H, s, 6α-Me); 0.88 (3H, t, J=6.9, CH₂CH₃).

4.5 Synthesis of ALL00129 (Δ⁹-Tetrahydrocannabinol3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate)

To a stirred solution of THC (23.1 mg, 0.07346 mmol) and5-carboxy-2,2,5-trimethyl-1,3-dioxane (15.4 mg, 0.08815 mmol) indichloromethane (0.4 mL) was added to 4-dimethylaminopyridine (1.5 mg,0.007346 mmol) followed by N,N′-dicyclohexylcarbodiimide (20.5 mg,0.09917 mmol). The mixture was stirred at ambient temperature for 2 h.Additional portions of 5-carboxy-2,2,5-trimethyl-1,3-dioxane (15 mg,0.08611 mmol), 4-dimethylaminopyridine (3 mg, 0.0145 mmol) andN,N′-dicyclohexylcarbodiimide (18 mg, 0.08724 mmol) were added andstirred for an additional 3.5 h. The mixture was diluted with hexane(0.4 mL), filtered, concentrated under a reduced pressure andchromatographed on silica gel with hexane-ethyl acetate (gradient 10:1,8:1, 5:1) to afford THC 3-hydroxy-2-(hydroxymethyl)-2-methylpropanoateacetonide (25.7 mg, 55%) as an oil.

Zinc trifluoromethanesulfanate (25 mg) was added to a solution of THC3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate acetonide (20.56 mg,0.04369 mmol) and 1-octanethiol (100 μL) in dichloromethane (1.4 mL).The mixture was stirred at ambient temperature for 3 h. The mixture wasfiltered, the filtrate was concentrated and the residue was purified bynormal phase HPLC (ZORBAX RX-SIL, 5 μm, 9.4×250 mm, hexane-ethyl acetate(1:1)) to afford 8.36 mg (44%) of THC3-hydroxy-2-(hydroxymethyl)-2-methylpropanoate (ALL00129) as an oil.LC-MS was as follows: 431.201 (M+H⁺, 100%), 315.158 (92%).

4.6 Synthesis of ALL00130 (Δ⁹-Tetrahydrocannabinol glycinate)

N-(2-nitrophenylsulfenyl)glycine was released from dicyclohexylammoniumsalt by extraction from pH 3.5 citrate buffer with dichloromethane.

The same procedure as for ALL00134 (total reaction time 8 h), startingfrom THC (20.6 mg), N-(2-nitrophenylsulfenyl)glycine (18.1 mg),N,N′-dicyclohexylcarbodiimide (19 mg) and 4-dimethylaminopyridine (0.8mg) in dichloromethane, with subsequent additions (in three portions) ofN-(2-nitrophenylsulfenyl)glycine (25 mg) andN,N′-dicyclohexylcarbodiimide (26 mg) afforded, after normal phase HPLC(ZORBAX RX-SIL, 5μm, 9.4×250 mm, hexane-ethyl acetate 70:30), 5.1 mg ofTHC N-(2-nitrophenylsulfenyl)glycinate as a yellow oil.

THC N-(2-nitrophenylsulfenyl)glycinate (6.1 mg, 0.0116 mmol) wasdissolved at ambient temperature in dry dichloromethane containing 10%(v/v) of thiophenol and 1.5% (v/v) of TFA (100 μL). After 5 min themixture was quenched by addition of 120 μL 3% triethylamine in DCM (at0° C.). The solution of crude product was chromatographed directly onsilica gel with dichloromethane-methanol (gradient 1:0, 20:1, 10:1,5:1). The combined fractions containing the product were diluted withchloroform, concentrated at 25° C. to ˜3 mL, diluted with chloroform andconcentrated again to ˜0.5 mL. The solution of product was diluted withchloroform again (˜5 mL) and concentrated to dryness. Remaining oil wasimmediately dissolved in chloroform, concentrated to dryness (2.49 mg,58%), and immediately dissolved in chloroform to afford a stock solutionof THC glycinate (ALL00130) stored at −20° C.

For ALL00130, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.56 (1H,d, J=1.7, H−4); 6.41 (1H, d, J=1.8, H−2); 5.88-5.92 (1H, m, H−10); 3.70(2H, AB system, COCH₂); 3.00-3.09 (1H, m, H−10a); 2.46-2.55 (2H, m);2.10-2.20 (2H, m); 1.85-1.98 (1H, m); 1.62-1.73 (4H, m); 1.50-1.62 (5H,m); 1.41 (3H, s, 6β-Me); 1.23-1.40 (5H, m); 1.09 (3H, s, 6α-Me); 0.88(3H, t, J=7.0, CH₂CH₃).

4.7 Synthesis of ALL00133 (Δ9-Tetrahydrocannabinol β-alaninate)

The same procedure as for ALL00134 (reaction time 3 h), starting fromTHC (31.4 mg, 0.10 mmol), N-(2-nitrophenylsulfenyl)-β-alanine (36.6 mg,0.13 mmol), N,N′-dicyclohexylcarbodiimide (34 mg, 0.165 mmol) and4-dimethylaminopyridine (5.1 mg, 0.025 mmol) in dichloromethane (0.5 mL)afforded, after silica gel chromatography with hexane-ethyl acetate(gradient 10:1, 6:1), 42.2 mg (78%) of THCN-(2-nitrophenylsulfenyl)-β-alaninate as a yellow oil.

THC N-(2-nitrophenylsulfenyl)-β-alaninate (35.8 mg, 0.0665 mmol) wasdissolved at ambient temperature in dry dichloromethane containing 10%(v/v) of thiophenol and 1.5% (v/v) of TFA (150 μL). After 10 min themixture was quenched by addition of 180 μL 3% triethylamine in DCM (at0° C.). The solution of crude product was chromatographed directly onsilica gel with dichloromethane-methanol (gradient 1:0, 30:1, 20:1,10:1, 7:1). The combined fractions containing the product were dilutedwith chloroform, concentrated at 25° C. to ˜3 mL, diluted withchloroform and concentrated again to ˜0.5 mL. The solution of productwas diluted with chloroform again (˜5 mL) and concentrated to dryness.The remaining oil was immediately dissolved in chloroform, concentratedto dryness (11.47 mg, 45%), and immediately dissolved in chloroform toafford a stock solution of THC β-alaninate (ALL00133) stored at −20° C.

For ALL00133, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.55 (1H,d, J=1.5, H−4); 6.41 (1H, d, J=1.5, H−2); 5.93-5.97 (1H, m, H−10);2.98-3.16 (3H, m, H−10a and CH₂N); 2.66-2.84 (2H, m, COCH₂); 2.45-2.53(2H, m); 2.10-2.20 (2H, m); 1.75-1.99 (3H, m); 1.62-1.73 (4H, m);1.50-1.62 (2H, m); 1.41 (3H, s, 6β-Me); 1.23-1.40 (5H, m); 1.09 (3H, s,6α-Me); 0.88 (3H, t, J=6.9, CH₂CH₃).

4.8 Synthesis of ALL00134 (Δ9-Tetrahydrocannabinol(S)-2,3-dihydroxypropanoate)

To a stirred solution of THC (31.4 mg, 0.1 mmol) and(S)-4-carboxy-2,2-dimethyl-1,3-dioxolane (22.1 mg, 0.13 mmol) indichloromethane (0.4 mL), 4-dimethylaminopyridine (5.2 mg, 0.025 mmol)was added followed by N,N′-dicyclohexylcarbodiimide (34.0 mg, 0.165mmol). The mixture was stirred at ambient temperature for 2 h. Themixture was diluted with hexane (0.4 mL), filtered, concentrated under areduced pressure and chromatographed on silica gel with hexane-ethylacetate (gradient 30:1, 20:1) to afford THC (S)-2,3-dihydroxypropanoateacetonide (22.7 mg, 51%) as an oil.

Zinc trifluoromethanesulfanate (10 mg, 0.0275 mmol) was added to asolution of THC (S)-2,3-dihydroxypropanoate acetonide (26.9 mg, 0.0532mmol) and 1-octanethiol (93.4 mg, 111 μL, 0.6385 mmol) indichloromethane (1 mL) and the mixture was stirred at ambienttemperature for 21 h. The mixture was filtered, the filtrate wasconcentrated and the residue was chromatographed on silica gel withhexane-ethyl acetate (gradient 4:1, 3:1, 2:1) to afford 18.1 mg (84%) ofTHC (S)-2,3-dihydroxypropanoate (ALL00134) as an oil.

For ALL00134, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.59 (1H,d, J=1.7, H−4); 6.44 (1H, d, J=1.8, H−2); 5.85-5.89 (1H, m, H−10);4.50-4.55 (1H, m); 4.00-4.14 (2H, m); 3.11 (1H, d, J=5.7); 3.02-3.10(1H, m, H−10a); 2.47-2.54 (2H, m); 2.19 (1H, t, J=6.8); 2.11-2.19 (2H,m); 1.87-1.94 (1H, m); 1.62-1.71 (4H, m); 1.52-1.62 (2H, m); 1.41 (3H,s, 6β-Me); 1.23-1.39 (5H, m); 1.09 (3H, s, 6α-Me); 0.88 (3H, t, J=6.9,CH₂ CH ₃).

4.9 Synthesis of ALL00138 (Δ⁹-Tetrahydrocannabinol(S)-2,3-dihydroxypropyl carbonate)

To a stirred solution of (R)-(−)-Solketal (22.2 mg, 0.168 mmol) indichloromethane (0.4 mL) at 0° C. under an argon atmosphere,triethylamine (17.7 mg, 24.4 μL, 0.175 mmol) was added, followed bytriphosgene (16.6 mg, 0.056 mmol) as stirring continued at 0° C. for 4h. The mixture was subsequently transferred to a solution of THC (44.0mg, 0.14 mmol) and triethylamine (18.4 mg, 25.4 μL, 0.182 mmol) indichloromethane (0.4 mL) under an argon atmosphere at 0° C. withstirring. Stirring continued at ambient temperature for 2 h. The mixturewas diluted with ethyl acetate (2 mL) and filtered. The filtrate wasconcentrated, dissolved in ethyl acetate (1 mL) and concentrated again.The residue was chromatographed on silica gel with hexane-ethyl acetate(gradient 30:1, 20:1, 10:1) to afford 34.5 mg (52%) of THC(S)-2,3-dihydroxypropyl carbonate acetonide.

Zinc trifluoromethanesulfanate (12.1 mg, 0.0333 mmol) was added to asolution of THC (S)-2,3-dihydroxypropyl carbonate acetonide (30.5 mg,0.06447 mmol) and 1-octanethiol (94.3 mg, 112 μL, 0.6447 mmol) indichloromethane (1 mL) and the mixture was stirred at ambienttemperature for 17 h. Mixture was filtered, filtrate was concentratedand the residue was chromatographed on silica gel with hexane-ethylacetate (gradient 3:1, 2:1, 1:1) to afford 18.8 mg (67%) of THC(S)-2,3-dihydroxypropyl carbonate (ALL00138) as an oil.

For ALL00138, the ¹H NMR (400 MHz, CDCl₃) was as follows: δ□=6.58 (1H,d, J=1.7, H−4); 6.50 (1H, d, J=1.8, H−2); 5.96-6.00 (1H, m, H−10);4.27-4.41 (2H, m); 4.00-4.08 (1H, m); 3.64-3.81 (2H, m); 3.11-3.19 (1H,m, H-l0a); 2.46-2.52 (3H, m); 2.11-2.19 (2H, m); 1.85-1.98 (2H, m);1.62-1.72 (4H, m); 1.52-1.62 (2H, m); 1.41 (3H, s, 6β-Me); 1.23-1.40(5H, m); 1.09 (3H, s, 6α-Me); 0.88 (3H, t, J=7.0, CH₂CH₃).

4.10 Synthesis of ALL00144 (Δ⁹-Tetrahydrocannabinol(R)-2,3-dihydroxypropyl carbonate)

The same procedure as for ALL00134 starting from THC (42.79 mg, 0.136mmol), (R)-4-carboxy-2,2-dimethyl-1,3-dioxolane (23.85 mg, 0.163 mmol),N,N′-dicyclohexylcarbodiimide (39.2 mg, 0.190 mmol) and4-dimethylaminopyridine (3.3 mg, 0.027 mmol) in dichloromethaneafforded, after silica gel chromatography with hexane-ethyl acetate 9:1,46.96 mg (78%) of THC (R)-2,3-dihydroxypropanoate acetonide as an oil.

Zinc trifluoromethanesulfanate (25 mg) was added to a solution of THC(R)-2,3-dihydroxypropanoate acetonide (46.96 mg) and 1-octanethiol (100μL) in dichloromethane (1.6 mL) and the mixture was stirred at ambienttemperature overnight. Mixture was filtered, filtrate was concentratedand the residue was chromatographed using normal phase HPLC (ZORBAXRX-SIL, 5 μm, 9.4×250 mm, hexane-ethyl acetate 65:35) to afford 11.85 mg(28%) of THC (R)-2,3-dihydroxypropanoate (ALL00144) as an oil. LC-MS wasas follows: 403.137 (M+H⁺, 100%), 315.142 (61%).

5.0 Plasma Stability Studies

Approximately 1 mg/mL of stock solution of each prodrug was prepared in100 μL of ethanol and 900 μL of acetonitrile. Ten μL of stock was spikedinto 1 mL of plasma and vortexed. The samples were kept sealed in anamber vial and samples were obtained to analyze for bioconversion toparent drug.

6.0 Preparation of Drug Formulations

6.1 Preparation of Receiver Fluid

The receiver fluid was prepared by measuring 600 mL of nanopure H₂O intoa graduated cylinder. The H₂O was filtered through a 0.2μ filter(Millipore, Billerica, Mass.). 50 mg of gentamicin was added to thefiltered H₂O and 400 mL of PEG 400 was added.

6.2 Preparation of Drug Formulations

The prodrugs were made up in a solution of 90:8:2 PG:H₂O:IPM. For thissolution, the appropriate amount of drug was weighed into a glasssilanized culture tube and IPM was added, then 50 μL of PG to coat thedrug, then an additional 247 μL PG was added and the donor solution wasvortexed again. Finally 26 μL of water was added.

6.3 Permeation Experiments

(i) Dermatomed skin harvested from abdominoplasty which was stored at−20° C. was used for the experiments. A PermeGear flow-through (In-Line,Hellertown, Pa.) diffusion cell system was used for the skin permeationstudies.

(ii) Diffusion cells were kept at 32° C. with a circulating water bath.Human epidermal skin was arranged in the diffusion cell with stratumcorneum (upper layer of skin) facing the donor compartment. Permeationarea of the skin was 0.95 cm². Data was collected from a human skindonor with three diffusion cells per treatment.

(iii) Receiver solution was 40% aqueous PEG 400 and flow rate wasadjusted to 0.8 mL/h. Each cell was charged with 90-100 μL of therespective drug formulation (donor solution). The formulation wasapplied to ensure complete coverage. Diffusion cells were covered with astopper for the duration of the study.

(iv) Samples were collected into scintillation vials in 3 h incrementsfor 24 h or 1.5 h for 12 h, then 3 h until 24 h. All the samples werestored at 4° C. until extracted. An aliquot (500 μL) of the 40% PEG 400diffusion sample was placed into a silanized HPLC vial and 500 μL ofacetonitrile was added to the sample, capped and vortexed.

(v) At the end of the experiment, the skin tissue was removed from thediffusion cell, rinsed with nanopure water, and blotted dry with a papertowel. The skin was tape stripped twice using book tape (Scotch™, 3M,St. Paul, Minn.) to remove drug formulation adhering to the tissuesurface. The area of skin in contact with the drug was excised, choppedup and placed in a pre-weighed scintillation vial. Ten mL ofacetonitrile was added to the vial and drug was extracted from the skinby shaking at room temperature overnight. The samples were eitherinjected directly onto the HPLC or samples were diluted 10× withadditional acetonitrile before analyzed by HPLC.

(vi) At the end of the experiment, a 10 μL aliquot of donor solution wasremoved and added to a scintillation vial containing 10 mL ofacetonitrile. The vials were vortexed and then sonicated for 15 min. Analiquot of 1 mL was removed and transferred into a silanized HPLC vialfor analysis.

7.0 Analytical Method

Column Brownlee ® C₈ reversed phase Spheri 5 μm, (4.6 × 220 mm) columnwith a Brownlee ® C₈ reversed phase 7 μm (3.2 × 150 mm) guard column orSymmetry ®C₁₈ 5 μm (2.1 × 150 mm) column with a Sentry Semmetry ®C₁₈ 3.5μm (2.1 × 10 mm) guard column Mobile 70:30 acetonitrile:0.05%trifluroacetic phase acid with 5% acetonitrile, 80:20 acetonitrile:0.05%trifluroacetic acid with 5% acetonitrile, 90:10 acetonitrile:0.05%trifluroacetic acid with 5% acetonitrile, or 50:50→90:10→50:50(gradient) acetonitrile:0.05% trifluroacetic acid with 5% acetonitrileFlow rate 1.0 mL/min or 1.5 mL/min Wavelength 210 nm Injection 100 μL(diffusion samples and respective standards) volume 20 μL (skin samples,donor samples, and respective standards), skin samples were eitherinjected directly onto the column or they were diluted 10x withadditional acetonitrile before they were injected onto the column Runtime 9-16 min Retention Δ⁹-tetrahydrocannabinol = 6.0-6.1, 6.7, 7.9, 8.7min times ALL00117 = 8.0 min ALL00118 = 13.9 min ALL00126 = 5.6 minALL00127 = 4.4 min ALL00129 = 4.9, 6.6 min ALL00134 = 4.2-4.3 minALL00138 = 4.3 min ALL00144 = 4.3 min

8.0 Data Analysis

The cumulative quantity of drug collected in the receiver compartmentwas plotted as a function of time. Flux value for a given experiment wasobtained from the slope of a steady state portion of the cumulativeamount of drug permeated versus time plot. Lag time was obtained fromthe x-intercept of the steady state portion of the cumulative amount ofdrug permeated vs. time plot. The combined results of the deliveredprodrug and Δ⁹-tetrahydrocannabinol from the prodrug are listed as“total Δ⁹-tetrahydrocannabinol.” These values represent the data astotal Δ⁹-tetrahydrocannabinol equivalents delivered in the form ofΔ⁹-tetrahydrocannabinol and/or prodrug.

Section III. Tables

TABLE 15 Plasma stability of Δ⁹-tetrahydrocannabinol prodrugs % Prodrugat time (h) Prodrug 0.1 0.5 1 2 2.5 3 3.5 5 24 ALL00117 100 — 35 — 7 — 5— — ALL00118 100 — 94 86 81 — — — 15 ALL00126 100 — 3 — 1 — 1 — —ALL00127 100 — 100 — 91 — 85  — — ALL00129 100 — 100 — — 98 — — 83ALL00134 96 61 — 15 — — — 0.8  0 ALL00138 30  0 — — — — — — —

TABLE 16 Δ⁹-Tetrahydrocannabinol and Δ⁹-tetrahydrocannabinol prodrugsMolecular Molecular Compound formula weight Δ⁹-tetrahydrocannabinolC₂₁H₃₀O₂ 314.46 ALL00117 C₃₀H₄₆O₇ 518.68 ALL00118 C₂₅H₃₇NO₃ 399.57ALL00126 C₂₅H₃₆O₆ 432.55 ALL00127 C₂₆H₃₉NO₄ 429.59 ALL00129 C₂₆H₃₈O₅430.58 ALL00130 C₂₃H₃₃NO₃ 371.51 ALL00133 C₂₄H₃₅NO₃ 385.54 ALL00134C₂₄H₃₄O₅ 402.52 ALL00138 C₂₅H₃₆O₆ 432.55 ALL00144 C₂₄H₃₄O₅ 402.52

TABLE 17 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2), ALL00117 (n= 3), ALL00118 (n = 3) and ALL00126 (n = 2) with 90:8:2 PG:H₂O:IPM donorsolution 24 h 24 h Flux Lag skin conc cumulative (nmol/ Flux timeCompound (μmol/g) amt (nmol) cm²/h) enhancement (h)Δ⁹-tetrahydrocannabinol (THC) 6.1 ± 1.9 16.3 ± 0.3  1.0 ± 0.3 —  5.8 ±5.9 total Δ⁹-tetrahydrocannabinol * 7.3 ± 1.8 3.7 ± 1.0 0.5 ± 0.1 0.4515.4 ± 0.3 ALL00117 7.3 ± 1.8 3.0 ± 0.3 0.4 ± 0.1 15.1 ± 0.2 THC fromALL00117 ND 0.7 ± 0.7 — — total Δ⁹-tetrahydrocannabinol * 13.5 ± 5.8 11.4 ± 0.7  0.9 ± 0.1 0.90 11.6 ± 0.2 ALL00118 9.8 ± 5.2 5.8 ± 0.4 0.5 ±0.0 12.8 ± 0.1 THC from ALL00118 3.7 ± 0.6 5.6 ± 0.5 0.4 ± 0.0 10.2 ±0.3 total Δ⁹-tetrahydrocannabinol * 24.5 ± 5.8  89.4 ± 14.4 7.1 ± 0.27.13 10.6 ± 1.9 ALL00126 17.8 ± 4.8  69.7 ± 10.7 5.7 ± 0.0 10.8 ± 2.1THC from ALL00126 6.7 ± 1.0 19.7 ± 3.7  1.4 ± 0.2  9.7 ± 1.1

TABLE 18 Permeation data of Δ⁹-tetrahydrocannabinol (n = 1), ALL00129 (n= 3), and ALL00138 (n = 3) with 90:8:2 PG:H₂O:IPM donor solution 24 h 24h Flux Lag skin conc cumulative (nmol/ Flux time Compound (μmol/g) amt(nmol) cm²/h) enhancement (h) Δ⁹-tetrahydrocannabinol (THC) 17.4 ± 9.2 53.3 ± 0.0 3.2 ± 0.0 — 6.2 ± 0.0 total Δ⁹-tetrahydrocannabinol * 19.6 ±12.6 74.2 ± 8.1 4.8 ± 0.7 1.53 7.8 ± 1.3 ALL00129 19.6 ± 12.6 74.2 ± 8.14.8 ± 0.7 7.8 ± 1.3 THC from ALL00129 ND ND — — totalΔ⁹-tetrahydrocannabinol * 21.3 ± 7.3  37.6 ± 8.3 2.5 ± 0.5 0.79 8.1 ±0.0 ALL00138 7.2 ± 4.8 18.2 ± 1.4 1.0 ± 0.0 5.9 ± 1.4 THC from ALL0013814.1 ± 2.8  19.4 ± 6.9 1.4 ± 0.5 9.7 ± 0.4

TABLE 19 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2), ALL00127 (n= 3), ALL00134 (n = 3) and ALL00144 (n = 2) with 90:8:2 PG:H₂O:IPM donorsolution 24 h 24 h Flux Lag skin conc cumulative (nmol/ Flux timeCompound (μmol/g) amt (nmol) cm²/h) enhancement (h)Δ⁹-tetrahydrocannabinol (THC) 23.3 ± 1.7  29.8 ± 3.3 2.0 ± 0.3 — 8.7 ±0.3 total Δ⁹-tetrahydrocannabinol * 32.9 ± 27.7 15.6 ± 2.8 1.1 ± 0.30.53 8.6 ± 2.2 ALL00127 ND ND — — THC from ALL00127 32.9 ± 27.7 15.6 ±2.8 1.1 ± 0.3 8.6 ± 2.2 total Δ⁹-tetrahydrocannabinol * 25.3 ± 12.6137.2 ± 5.8  8.5 ± 0.3 4.16 7.0 ± 0.2 ALL00134 24.5 ± 12.3 128.6 ± 5.1 8.0 ± 0.3 7.0 ± 0.1 THC from ALL00134 0.8 ± 0.2  8.6 ± 1.0 0.5 ± 0.0 6.5± 2.3 total Δ⁹-tetrahydrocannabinol * 69.7 ± 37.3 149.0 ± 57.9 9.3 ± 3.54.56 7.2 ± 0.2 ALL00144 65.5 ± 39.5 137.9 ± 55.2 8.6 ± 3.4 7.2 ± 0.1 THCfrom ALL00144 4.1 ± 2.2 11.1 ± 2.7 0.7 ± 0.1 6.6 ± 1.8

Example 4

Section I. Summary

The objective was to synthesize Δ⁹-tetrahydrocannabinol prodrugs andassess the permeation of Δ⁹-tetrahydrocannabinol and its prodrugsthrough human abdominal skin in vitro. One Δ⁹-tetrahydrocannabinolprodrug was synthesized and tested. Flow through diffusion cells wereused for the permeation studies. The receiver used for the permeationstudies was a 40% aqueous PEG 400. The donor solution was comprised of90:8:2 PG:H₂O:IPM. The flux and lag time values ofΔ⁹-tetrahydrocannabinol and Δ⁹-tetrahydrocannabinol prodrugs wereobtained from the permeation profiles. Drug accumulation in the skinafter a 24 h diffusion experiment was determined as μmol/g wet tissueweight.

Section II. Methodology

1.0 Purpose: The purpose was to synthesize Δ⁹-tetrahydrocannabinolprodrugs and assess the human skin permeation of Δ⁹-tetrahydrocannabinoland Δ⁹-tetrahydrocannabinol prodrugs in vitro. The following compoundwas synthesized:

2.0 Skin Details

The skin samples used in the following experiments were supplied byCooperative Human Tissue Network. The skin samples used herein werefrozen at −20° C. for less than six months.

3.0 In Vitro Skin Permeation Studies

3.1 Preparation of Receiver Fluid

The receiver fluid was prepared by measuring 600 mL of nanopure H₂O intoa graduated cylinder. The H₂O was filtered through a 0.2μ filter(Millipore, Billerica, MA) and 400 mL of PEG 400 was added.

3.2 Preparation of Drug Formulation

The drug formulation was made up in 90:8:2 PG:H₂O:IPM. For the solution,the appropriate amount of drug was weighed into a glass silanizedculture tube and 7 μL of IPM was added. Next, 50 μL of PG was added andvortexed to get the drug into solution, then the remaining PG (247 μL)was added. Water was added last. Both donor solutions were saturated.

3.3 Permeation Experiments

Dermatomed skin harvested from abdominoplasty, stored at −20°, was usedfor the experiments. A PermeGear flow-through (In-Line, Hellertown, Pa.)diffusion cell system was used for the skin permeation studies.

Diffusion cells were kept at 32° C. with a circulating water bath. Humanepidermal skin was arranged in the diffusion cell with stratum corneum(upper layer of skin) facing the donor compartment. Permeation area ofthe skin was 0.95 cm². Data was collected from a human skin donor withthree diffusion cells per treatment.

The receiver solution was 40% aqueous PEG 400 and flow rate was adjustedto 0.8 mL/h. Each cell was charged with 100 μL of the respective drugformulation (donor solution). The formulation was applied to ensurecomplete coverage. Diffusion cells were covered with a stopper for theduration of the study.

Samples were collected into scintillation vials in 3 h increments for 24h. All the samples were stored at 4° C. until extracted. An aliquot (500μL) of the 40% PEG 400 diffusion sample was placed into a silanized HPLCvial and 500 μL of acetonitrile was added to the sample, capped andvortexed.

At the end of the experiment, the skin tissue was removed from thediffusion cell, rinsed with nanopure water, and blotted dry with a papertowel. The skin was tape stripped twice using book tape (Scotch™, 3M,St. Paul, Minn.) to remove drug formulation adhering to the tissuesurface. The area of skin in contact with the drug was excised, choppedup and placed in a pre-weighed scintillation vial. Ten mL ofacetonitrile was added to the vial and drug was extracted from the skinby shaking at room temperature overnight. The samples were analyzed byHPLC.

At the end of the experiment, a 10 μL aliquot of donor solution wasremoved and added to a scintillation vial containing 10 mL ofacetonitrile. The vials were vortexed and then sonicated for 15 min. Analiquot of 1 mL was removed and transferred into a silanized HPLC vialfor analysis.

4.0 Analytical Method

Column Brownlee ® C₈ reversed phase Spheri 5 μm, (4.6 × 220 mm) columnwith a Brownlee ® C₈ reversed phase 7 μm (3.2 × 150 mm) guard columnMobile 85:15 acetonitrile:0.05% trifluroacetic phase acid with 5%acetonitrile Flow rate 1.5 mL/min Wavelength 210 nm Injection 100 μL(diffusion samples and volume respective standards) 20 μL (skin samples,donor samples, and respective standards) Run time 21 min RetentionΔ⁹-tetrahydrocannabinol = 5.1 min times ALL00153 = 18.9 min

5.0 Data Analysis

The cumulative quantity of drug collected in the receiver compartmentwas plotted as a function of time. The flux value for a given experimentwas obtained from the slope of a steady state portion of the cumulativeamount of drug permeated vs. time plot. Lag time was obtained from thex-intercept of the steady state portion of the cumulative amount of drugpermeated vs. time plot. The combined results of the delivered prodrugand Δ⁹-tetrahydrocannabinol from the prodrug are listed as “totalΔ⁹-tetrahydrocannabinol.” These values represent the data as totalΔ⁹-tetrahydrocannabinol equivalents delivered in the form ofΔ⁹-tetrahydrocannabinol and/or prodrug.

Section III. Tables

TABLE 20 Permeation data of Δ⁹-tetrahydrocannabinol (n = 2) and ALL00153(n = 3) in 90:8:2 PG:H₂O:IPM donor solution 24 h 24 h Flux Lag skin conccumulative (nmol/ Flux time Compound (μmol/g) amt (nmol) cm²/h)enhancement (h) Δ⁹-tetrahydrocannabinol (THC)  8.5 ± 3.5 15.7 ± 4.5 1.1± 0.3 —  9.0 ± 0.7 total Δ⁹-tetrahydrocannabinol * 11.3 ± 3.4 23.7 ± 6.11.9 ± 0.5 1.75 10.9 ± 0.3 ALL00153  0.6 ± 0.1 ND — — THC from ALL0015310.9 ± 3.1 23.7 ± 6.1 1.9 ± 0.5 10.9 ± 0.3 * total THC = totalΔ⁹-tetrahydrocannabmol equivalents delivered in the form ofΔ⁹-tetrahydrocannabinol and/or prodrug

All references, including publications, patent applications, andpatents, cited herein are hereby incorporated by reference to the sameextent as if each reference were individually and specifically indicatedto be incorporated by reference and were set forth in its entiretyherein.

The use of the terms “a” and “an” and “the” and similar references inthe context of this disclosure (especially in the context of thefollowing claims) are to be construed to cover both the singular and theplural, unless otherwise indicated herein or clearly contradicted bycontext. All methods described herein can be performed in any suitableorder unless otherwise indicated herein or otherwise clearlycontradicted by context. The use of any and all examples, or exemplarylanguage (e.g., such as, preferred, preferably) provided herein, isintended merely to further illustrate the content of the disclosure anddoes not pose a limitation on the scope of the claims. No language inthe specification should be construed as indicating any non-claimedelement as essential to the practice of the present disclosure.

Alternative embodiments of the claimed disclosure are described herein,including the best mode known to the inventors for practicing theclaimed invention. Of these, variations of the disclosed embodimentswill become apparent to those of ordinary skill in the art upon readingthe foregoing disclosure. The inventors expect skilled artisans toemploy such variations as appropriate (e.g., altering or combiningfeatures or embodiments), and the inventors intend for the invention tobe practiced otherwise than as specifically described herein.

Accordingly, this invention includes all modifications and equivalentsof the subject matter recited in the claims appended hereto as permittedby applicable law. Moreover, any combination of the above describedelements in all possible variations thereof is encompassed by theinvention unless otherwise indicated herein or otherwise clearlycontradicted by context.

The use of individual numerical values are stated as approximations asthough the values were preceded by the word “about” or “approximately.”Similarly, the numerical values in the various ranges specified in thisapplication, unless expressly indicated otherwise, are stated asapproximations as though the minimum and maximum values within thestated ranges were both preceded by the word “about” or “approximately.”In this manner, variations above and below the stated ranges can be usedto achieve substantially the same results as values within the ranges.As used herein, the terms “about” and “approximately” when referring toa numerical value shall have their plain and ordinary meanings to aperson of ordinary skill in the art to which the disclosed subjectmatter is most closely related or the art relevant to the range orelement at issue. The amount of broadening from the strict numericalboundary depends upon many factors. For example, some of the factorswhich may be considered include the criticality of the element and/orthe effect a given amount of variation will have on the performance ofthe claimed subject matter, as well as other considerations known tothose of skill in the art. As used herein, the use of differing amountsof significant digits for different numerical values is not meant tolimit how the use of the words “about” or “approximately” will serve tobroaden a particular numerical value or range. Thus, as a generalmatter, “about” or “approximately” broaden the numerical value. Also,the disclosure of ranges is intended as a continuous range includingevery value between the minimum and maximum values plus the broadeningof the range afforded by the use of the term “about” or “approximately.”Thus, recitation of ranges of values herein are merely intended to serveas a shorthand method of referring individually to each separate valuefalling within the range, unless otherwise indicated herein, and eachseparate value is incorporated into the specification as if it wereindividually recited herein.

It is to be understood that any ranges, ratios and ranges of ratios thatcan be formed by, or derived from, any of the data disclosed hereinrepresent further embodiments of the present disclosure and are includedas part of the disclosure as though they were explicitly set forth. Thisincludes ranges that can be formed that do or do not include a finiteupper and/or lower boundary. Accordingly, a person of ordinary skill inthe art most closely related to a particular range, ratio or range ofratios will appreciate that such values are unambiguously derivable fromthe data presented herein.

1. A compound having the formula:

wherein R₁ is selected from an ester, a carbonate, a carbamate and aphosphate. 2-20. (canceled)